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Sample records for acquired cns gene

  1. Clinical Applications Involving CNS Gene Transfer

    PubMed Central

    Kantor, Boris; McCown, Thomas; Leone, Paola; Gray, Steven J.

    2015-01-01

    Diseases of the central nervous system (CNS) have traditionally been the most difficult to treat by traditional pharmacological methods, due mostly to the blood–brain barrier and the difficulties associated with repeated drug administration targeting the CNS. Viral vector gene transfer represents a way to permanently provide a therapeutic protein within the nervous system after a single administration, whether this be a gene replacement strategy for an inherited disorder or a disease-modifying protein for a disease such as Parkinson's. Gene therapy approaches for CNS disorders has evolved considerably over the last two decades. Although a breakthrough treatment has remained elusive, current strategies are now considerably safer and potentially much more effective. This chapter will explore the past, current, and future status of CNS gene therapy, focusing on clinical trials utilizing adeno-associated virus and lentiviral vectors. PMID:25311921

  2. CNS myelination and PLP gene dosage.

    PubMed

    Woodward, K; Malcolm, S

    2001-08-01

    The phenomenon of gene dosage effects demonstrates that the mechanisms of some genetic diseases are best recognised at the genomic level. Classical gene mutation screening approaches utilising PCR are unsuccessful in unravelling the basis of disease because the gene sequence is unaltered and only the copy number is different. Techniques for detecting DNA dosage are required. Examples of haploinsufficiency and gene deletions are well documented, but increased gene dosage is also an important genetic mechanism in disorders involving myelin proteins in the central (CNS) and peripheral nervous system (PNS). Here we review the dosage effects and mutations of the proteolipid protein (PLP) gene that causes Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia Type 2 (SPG2) disorders of CNS myelination. Similarities are drawn with the peripheral neuropathies Charcot-Marie-Tooth disease Type 1 (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) that are also caused by dosage effects and mutations in a single myelin protein gene (peripheral myelin protein 22, PMP-22). We compare the different mutational mechanisms in man and analogous mouse models that suggest a function for PLP beyond its structural role in myelin. We focus on the increased dosage of the PLP gene that is the major cause of PMD and results from a submicroscopic duplication of Xq22. Other clinical phenotypes may arise from gene dosage imbalance with the potential effect of submicroscopic duplications and deletions of the genome being underestimated. Genome sequencing may identify intrinsic structural properties of the DNA with greater susceptibility to these rearrangements and thereby reflect structural changes in the genome. PMID:11535114

  3. Gene therapy for CNS diseases - Krabbe disease.

    PubMed

    Rafi, Mohammad A

    2016-01-01

    This is a brief report of the 19th Annual Meeting of the American Society of Gene and Cell Therapy that took place from May 4th through May 7th, 2016 in Washington, DC, USA. While the meeting provided many symposiums, lectures, and scientific sessions this report mainly focuses on one of the sessions on the "Gene Therapy for central nervous system (CNS) Diseases" and specifically on the "Gene Therapy for the globoid cell leukodystrophy or Krabbe disease. Two presentations focused on this subject utilizing two animal models of this disease: mice and dog models. Different serotypes of adeno-associate viral vectors (AAV) alone or in combination with bone marrow transplantations were used in these research projects. The Meeting of the ASGCT reflected continuous growth in the fields of gene and cell therapy and brighter forecast for efficient treatment options for variety of human diseases. PMID:27525222

  4. Pediatric acquired CNS demyelinating syndromes: Features associated with multiple sclerosis.

    PubMed

    Hintzen, Rogier Q; Dale, Russell C; Neuteboom, Rinze F; Mar, Soe; Banwell, Brenda

    2016-08-30

    Approximately one-third of children with an acquired demyelinating syndrome (ADS) will be diagnosed with multiple sclerosis (MS), either at onset according to the 2010 McDonald criteria, or on the basis of clinical or MRI evidence of relapsing disease, in the majority of patients within 2-4 years. ADS in adolescents, female patients, and patients with polyfocal deficits is associated with the highest likelihood of MS, while children with acute disseminated encephalomyelitis, those with documented preceding infection, and ADS presentation in young children more commonly portends a monophasic outcome. While pediatric MS associates with similar genetic risk alleles as have been documented in adult-onset MS, such associations are not diagnostically valuable at the individual level. The presence of antibodies directed against aquaporin-4 strongly supports a diagnosis of neuromyelitis optica, and should be assayed in children manifesting with severe optic neuritis, longitudinally extensive myelitis, or brainstem/hypothalamic syndromes. Further research will determine whether other antibody signatures are indicative of relapsing demyelination distinct from MS. PMID:27572864

  5. AAV-mediated gene transfer to the mouse CNS

    PubMed Central

    Stoica, Lorelei; Ahmed, Seemin S.

    2013-01-01

    Recombinant adeno associated virus (rAAV) vectors are great tools for gene transfer due to their ability to mediate long-term gene expression. Recombinant AAVs have been used at various ages of development with no apparent toxicity. There are multiple ways of delivering AAV vectors to the CNS, depending on the stage of development of the mouse. In neonates, intravascular injections into the facial vein are often used. In adults, direct injections into target regions of the brain are achieved with great spatiotemporal control through stereotaxic surgeries. Recently, discoveries of new AAV vectors with the ability to cross the blood brain barrier have made it possible to also target the adult CNS by intravascular injections. rAAVs have been successfully used as gene transfer vehicles in multiple animal models of CNS disorders, and several clinical trials are currently underway. PMID:23686825

  6. Gene therapy for CNS diseases – Krabbe disease

    PubMed Central

    Rafi, Mohammad A.

    2016-01-01

    Summary This is a brief report of the 19th Annual Meeting of the American Society of Gene and Cell Therapy that took place from May 4th through May 7th, 2016 in Washington, DC, USA. While the meeting provided many symposiums, lectures, and scientific sessions this report mainly focuses on one of the sessions on the "Gene Therapy for central nervous system (CNS) Diseases" and specifically on the "Gene Therapy for the globoid cell leukodystrophy or Krabbe disease. Two presentations focused on this subject utilizing two animal models of this disease: mice and dog models. Different serotypes of adeno-associate viral vectors (AAV) alone or in combination with bone marrow transplantations were used in these research projects. The Meeting of the ASGCT reflected continuous growth in the fields of gene and cell therapy and brighter forecast for efficient treatment options for variety of human diseases. PMID:27525222

  7. Viral vectors and delivery strategies for CNS gene therapy

    PubMed Central

    Gray, Steven J; Woodard, Kenton T; Samulski, R Jude

    2015-01-01

    This review aims to provide a broad overview of the targets, challenges and potential for gene therapy in the CNS, citing specific examples. There are a broad range of therapeutic targets, with very different requirements for a suitable viral vector. By utilizing different vector tropisms, novel routes of administration and engineered promoter control, transgenes can be targeted to specific therapeutic applications. Viral vectors have proven efficacious in preclinical models for several disease applications, spurring several clinical trials. While the field has pushed the limits of existing adeno-associated virus-based vectors, a next generation of vectors based on rational engineering of viral capsids should expand the application of gene therapy to be more effective in specific therapeutic applications. PMID:22833965

  8. Monoallelic Expression of Multiple Genes in the CNS

    PubMed Central

    Wang, Jinhui; Valo, Zuzana; Smith, David; Singer-Sam, Judith

    2007-01-01

    The inheritance pattern of a number of major genetic disorders suggests the possible involvement of genes that are expressed from one allele and silent on the other, but such genes are difficult to detect. Since DNA methylation in regulatory regions is often a mark of gene silencing, we modified existing microarray-based assays to detect both methylated and unmethylated DNA sequences in the same sample, a variation we term the MAUD assay. We probed a 65 Mb region of mouse Chr 7 for gene-associated sequences that show two distinct DNA methylation patterns in the mouse CNS. Selected genes were then tested for allele-specific expression in clonal neural stem cell lines derived from reciprocal F1 (C57BL/6×JF1) hybrid mice. In addition, using a separate approach, we directly analyzed allele-specific expression of a group of genes interspersed within clusters of OlfR genes, since the latter are subject to allelic exclusion. Altogether, of the 500 known genes in the chromosomal region surveyed, five show monoallelic expression, four identified by the MAUD assay (Agc1, p (pink-eyed dilution), P4ha3 and Thrsp), and one by its proximity to OlfR genes (Trim12). Thrsp (thyroid hormone responsive SPOT14 homolog) is expressed in hippocampus, but the human protein homolog, S14, has also been implicated in aggressive breast cancer. Monoallelic expression of the five genes is not coordinated at a chromosome-wide level, but rather regulated at individual loci. Taken together, our results suggest that at least 1% of previously untested genes are subject to allelic exclusion, and demonstrate a dual approach to expedite their identification. PMID:18074017

  9. Monoallelic expression of multiple genes in the CNS.

    PubMed

    Wang, Jinhui; Valo, Zuzana; Smith, David; Singer-Sam, Judith

    2007-01-01

    The inheritance pattern of a number of major genetic disorders suggests the possible involvement of genes that are expressed from one allele and silent on the other, but such genes are difficult to detect. Since DNA methylation in regulatory regions is often a mark of gene silencing, we modified existing microarray-based assays to detect both methylated and unmethylated DNA sequences in the same sample, a variation we term the MAUD assay. We probed a 65 Mb region of mouse Chr 7 for gene-associated sequences that show two distinct DNA methylation patterns in the mouse CNS. Selected genes were then tested for allele-specific expression in clonal neural stem cell lines derived from reciprocal F(1) (C57BL/6xJF1) hybrid mice. In addition, using a separate approach, we directly analyzed allele-specific expression of a group of genes interspersed within clusters of OlfR genes, since the latter are subject to allelic exclusion. Altogether, of the 500 known genes in the chromosomal region surveyed, five show monoallelic expression, four identified by the MAUD assay (Agc1, p (pink-eyed dilution), P4ha3 and Thrsp), and one by its proximity to OlfR genes (Trim12). Thrsp (thyroid hormone responsive SPOT14 homolog) is expressed in hippocampus, but the human protein homolog, S14, has also been implicated in aggressive breast cancer. Monoallelic expression of the five genes is not coordinated at a chromosome-wide level, but rather regulated at individual loci. Taken together, our results suggest that at least 1% of previously untested genes are subject to allelic exclusion, and demonstrate a dual approach to expedite their identification. PMID:18074017

  10. Evolution of the CNS myelin gene regulatory program.

    PubMed

    Li, Huiliang; Richardson, William D

    2016-06-15

    Myelin is a specialized subcellular structure that evolved uniquely in vertebrates. A myelinated axon conducts action potentials many times faster than an unmyelinated axon of the same diameter; for the same conduction speed, the unmyelinated axon would need a much larger diameter and volume than its myelinated counterpart. Hence myelin speeds information transfer and saves space, allowing the evolution of a powerful yet portable brain. Myelination in the central nervous system (CNS) is controlled by a gene regulatory program that features a number of master transcriptional regulators including Olig1, Olig2 and Myrf. Olig family genes evolved from a single ancestral gene in non-chordates. Olig2, which executes multiple functions with regard to oligodendrocyte identity and development in vertebrates, might have evolved functional versatility through post-translational modification, especially phosphorylation, as illustrated by its evolutionarily conserved serine/threonine phospho-acceptor sites and its accumulation of serine residues during more recent stages of vertebrate evolution. Olig1, derived from a duplicated copy of Olig2 in early bony fish, is involved in oligodendrocyte development and is critical to remyelination in bony vertebrates, but is lost in birds. The origin of Myrf orthologs might be the result of DNA integration between an invading phage or bacterium and an early protist, producing a fusion protein capable of self-cleavage and DNA binding. Myrf seems to have adopted new functions in early vertebrates - initiation of the CNS myelination program as well as the maintenance of mature oligodendrocyte identity and myelin structure - by developing new ways to interact with DNA motifs specific to myelin genes. This article is part of a Special Issue entitled SI: Myelin Evolution. PMID:26474911

  11. Acquired Antibiotic Resistance Genes: An Overview

    PubMed Central

    van Hoek, Angela H. A. M.; Mevius, Dik; Guerra, Beatriz; Mullany, Peter; Roberts, Adam Paul; Aarts, Henk J. M.

    2011-01-01

    In this review an overview is given on antibiotic resistance (AR) mechanisms with special attentions to the AR genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance, attention is also paid to mobile genetic elements such as plasmids, transposons, and integrons, which are associated with AR genes, and involved in the dispersal of antimicrobial determinants between different bacteria. PMID:22046172

  12. Tetracycline resistance genes acquired at birth.

    PubMed

    Alicea-Serrano, Angela M; Contreras, Mónica; Magris, Magda; Hidalgo, Glida; Dominguez-Bello, Maria G

    2013-06-01

    Newborns acquire their first microbiota at birth. Maternal vaginal or skin bacteria colonize newborns delivered vaginally or by C-section, respectively (Dominguez-Bello et al. 2010 #884). We aimed to determine differences in the presence of four tetracycline (tet) resistance genes, in the microbes of ten newborns and in the mouth and vagina of their mothers, at the time of birth. DNA was amplified by PCR with primers specific for [tet(M), tet(O), tet(Q), and tet(W)]. Maternal vaginas harbored all four tet resistance genes, but most commonly tet(M) and tet(O) (63 and 38 %, respectively). Genes coding for tet resistance differed by birth mode, with 50 % of vaginally delivered babies had tet(M) and tet(O) and 16 and 13 % of infants born by C-section had tet(O) and tet(W), respectively. Newborns acquire antibiotic resistance genes at birth, and the resistance gene profile varies by mode of delivery. PMID:23483141

  13. Identification of acquired antimicrobial resistance genes

    PubMed Central

    Zankari, Ea; Hasman, Henrik; Cosentino, Salvatore; Vestergaard, Martin; Rasmussen, Simon; Lund, Ole; Aarestrup, Frank M.; Larsen, Mette Voldby

    2012-01-01

    Objectives Identification of antimicrobial resistance genes is important for understanding the underlying mechanisms and the epidemiology of antimicrobial resistance. As the costs of whole-genome sequencing (WGS) continue to decline, it becomes increasingly available in routine diagnostic laboratories and is anticipated to substitute traditional methods for resistance gene identification. Thus, the current challenge is to extract the relevant information from the large amount of generated data. Methods We developed a web-based method, ResFinder that uses BLAST for identification of acquired antimicrobial resistance genes in whole-genome data. As input, the method can use both pre-assembled, complete or partial genomes, and short sequence reads from four different sequencing platforms. The method was evaluated on 1862 GenBank files containing 1411 different resistance genes, as well as on 23 de-novo-sequenced isolates. Results When testing the 1862 GenBank files, the method identified the resistance genes with an ID = 100% (100% identity) to the genes in ResFinder. Agreement between in silico predictions and phenotypic testing was found when the method was further tested on 23 isolates of five different bacterial species, with available phenotypes. Furthermore, ResFinder was evaluated on WGS chromosomes and plasmids of 30 isolates. Seven of these isolates were annotated to have antimicrobial resistance, and in all cases, annotations were compatible with the ResFinder results. Conclusions A web server providing a convenient way of identifying acquired antimicrobial resistance genes in completely sequenced isolates was created. ResFinder can be accessed at www.genomicepidemiology.org. ResFinder will continuously be updated as new resistance genes are identified. PMID:22782487

  14. Adeno-Associated Virus-Based Gene Therapy for CNS Diseases

    PubMed Central

    Hocquemiller, Michaël; Giersch, Laura; Audrain, Mickael; Parker, Samantha; Cartier, Nathalie

    2016-01-01

    Gene therapy is at the cusp of a revolution for treating a large spectrum of CNS disorders by providing a durable therapeutic protein via a single administration. Adeno-associated virus (AAV)-mediated gene transfer is of particular interest as a therapeutic tool because of its safety profile and efficiency in transducing a wide range of cell types. The purpose of this review is to describe the most notable advancements in preclinical and clinical research on AAV-based CNS gene therapy and to discuss prospects for future development based on a new generation of vectors and delivery. PMID:27267688

  15. LIS1 Lissencephaly gene CNS expression: Relation to neuronal migration

    SciTech Connect

    Reiner, O. |; Gal-Gerber, O.; Sapir, T.

    1994-09-01

    Lis1 is the murine gene corresponding to human LIS1 gene involved in Miller-Dieker lissencephaly located on chromosome 17p13.3 as demonstrated by cDNA cloning, sequence analysis and genetic mapping. Lis1 expression was studied in developing mouse brain using in situ hybridization. At embryonic day 15, Lis1 expression was most prominently localized in the neuronal layer of the retina, the developing hippocampus, doral root ganglia, cranial ganglia and the thalamus. At postnatal day 5 a unique pattern of expression was detected in the developing cerebellum. Lis1 was expressed at high levels in the Purkinje cell layer when the granule cells were migrating through the Purkinje cell layer inwards. The expression of Lis1 in Purkinje cells in the adult is markedly reduced. Similarly, Lis1 was expressed in the ontogenetically older layers of the neocortex (layers 5 and 6) where younger neurons have to migrate through to settle in the superficial layers. Thus, at both sites a link between expression and neuronal migration was demonstrated. These studies on the expression pattern of Lis1 could be useful in understanding abnormalities in Miller-Dieker lissencephaly syndrome (MDS) patients.

  16. Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates.

    PubMed

    Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre; Zhu, Yanqing; Yu, Hongwei; Lin, Gloria; Choa, Ruth; Gurda, Brittney L; Bagel, Jessica; O'Donnell, Patricia; Sikora, Tracey; Ruane, Therese; Wang, Ping; Tarantal, Alice F; Casal, Margret L; Haskins, Mark E; Wilson, James M

    2015-08-01

    The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy. PMID:26022732

  17. Intrathecal Gene Therapy Corrects CNS Pathology in a Feline Model of Mucopolysaccharidosis I

    PubMed Central

    Hinderer, Christian; Bell, Peter; Gurda, Brittney L; Wang, Qiang; Louboutin, Jean-Pierre; Zhu, Yanqing; Bagel, Jessica; O'Donnell, Patricia; Sikora, Tracey; Ruane, Therese; Wang, Ping; Haskins, Mark E; Wilson, James M

    2014-01-01

    Enzyme replacement therapy has revolutionized the treatment of the somatic manifestations of lysosomal storage diseases (LSD), although it has been ineffective in treating central nervous system (CNS) manifestations of these disorders. The development of neurotrophic vectors based on novel serotypes of adeno-associated viruses (AAV) such as AAV9 provides a potential platform for stable and efficient delivery of enzymes to the CNS. We evaluated the safety and efficacy of intrathecal delivery of AAV9 expressing α-l-iduronidase (IDUA) in a previously described feline model of mucopolysaccharidosis I (MPS I). A neurological phenotype has not been defined in these animals, so our analysis focused on the biochemical and histological CNS abnormalities characteristic of MPS I. Five MPS I cats were dosed with AAV9 vector at 4–7 months of age and followed for 6 months. Treated animals demonstrated virtually complete correction of biochemical and histological manifestations of the disease throughout the CNS. There was a range of antibody responses against IDUA in this cohort which reduced detectable enzyme without substantially reducing efficacy; there was no evidence of toxicity. This first demonstration of the efficacy of intrathecal gene therapy in a large animal model of a LSD should pave the way for translation into the clinic. PMID:25027660

  18. Expression of planar cell polarity genes during development of the mouse CNS.

    PubMed

    Tissir, Fadel; Goffinet, André M

    2006-02-01

    Atypical cadherin (Celsr3) and the receptor Frizzled3 (Fzd3) are crucial for the development of axonal tracts in the mouse CNS. Celsr3 and Fzd3 are orthologues of the Drosophila'planar cell polarity' (PCP) genes flamingo/starry night (fmi/stan) and frizzled, respectively. Reasoning that Celsr3 and Fzd3 might interact with PCP orthologues in mammals like they do in flies, we used mRNA in situ hybridization to compare the expression of Celsr3 and Fzd3 with that of dishevelled 1, 2 and 3 (Dvl1-3), van gogh-like 1 and 2 (Vangl1, 2), and prickle-like 1 and 2 (Prickle1, 2), during mouse CNS development, from embryonic day 10.5 to postnatal day 21. With the relative exception of Vangl1, all genes were expressed in the developing CNS. Although Celsr3- and Fzd3-deficient mice have similar phenotypes, Fzd3 expression was more widespread than that of Celsr3. Vangl2 and Dvl2 were preferentially expressed in ventricular zones, in keeping with their role during neural tube closure, where they could be partners of Celsr1. Dvl1 had a broad expression, reminiscent of that of Celsr2, and may be involved in neural maintenance. A large overlap in the expression territories of Dvl genes suggested redundancy. Vangl1 and Prickle1 had expression canvases different from each other and from other candidates, indicating unrelated function. Like Celsr3, Dvl3 and Prickle2 were expressed more strongly in postmitotic neurons than in precursors. Thus, the analogy between the PCP and Celsr3-Fzd3 genetic networks is limited, but may include Dvl3 and/or Prickle2. PMID:16487141

  19. Microglial P2 Purinergic Receptor and Immunomodulatory Gene Transcripts Vary By Region, Sex, and Age in the Healthy Mouse CNS

    PubMed Central

    Crain, Jessica M.; Watters, Jyoti J.

    2016-01-01

    Inflammatory damage in many neurodegenerative diseases is restricted to certain regions of the CNS, and while microglia have long been implicated in the pathology of many of these disorders, information comparing their gene expression in different CNS regions is lacking. Here we tested the hypothesis that the expression of purinergic receptors, estrogen receptors and other neuroprotective and pro-inflammatory genes differed among CNS regions in healthy mice. Because neurodegenerative diseases vary in incidence by sex and age, we also examined the regional distribution of these genes in male and female mice of four different ages between 21 days and 12 months. We postulated that pro-inflammatory gene expression would be higher in older animals, and lower in young adult females. We found that microglial gene expression differed across the CNS. Estrogen receptor alpha (Esr1) mRNA levels were often lower in microglia from the brainstem/spinal cord than from the cortex, whereas tumor necrosis factor alpha (Tnfα) expression was several times higher. In addition, the regional pattern of gene expression often changed with animal age; for example, no regional differences in P2X7 mRNA levels were detected in 21 day-old animals, but at 7 weeks and older, expression was highest in cerebellar microglia. Lastly, the expression of some genes was sexually dimorphic. In microglia from 12 month-old animals, mRNA levels of inducible nitric oxide synthase, but not Tnfα, were higher in females than males. These data suggest that microglial gene expression is not uniformly more pro-inflammatory in males or older animals. Moreover, microglia from CNS regions in which neuronal damage predominates in neurodegenerative disease do not generally express more pro-inflammatory genes than microglia from regions less frequently affected. This study provides an in-depth assessment of regional-, sex- and age-dependent differences in key microglial transcripts from the healthy mouse CNS. PMID

  20. The Dural AV-Fistula (DAVF), the Most Frequent Acquired Vascular Malformation of the Central Nervous System (CNS).

    PubMed

    Wanke, I; Rüfenacht, D A

    2015-10-01

    Acquired arteriovenous malformations, such as is the case with dural arteriovenous fistulae (DAVF), are the consequence of a pathological new arterial ingrowth into venous spaces that reaches directly the venous lumen, without interposition of a capillary network, thereby creating an AV-shunt.The following concise text will provide elements in regards to diagnosis, indication for treatment discussion and choice of endovascular treatment (EVT) method. PMID:26308245

  1. An AUTS2-Polycomb complex activates gene expression in the CNS.

    PubMed

    Gao, Zhonghua; Lee, Pedro; Stafford, James M; von Schimmelmann, Melanie; Schaefer, Anne; Reinberg, Danny

    2014-12-18

    Naturally occurring variations of Polycomb repressive complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, autism susceptibility candidate 2 (AUTS2). Although AUTS2 is often disrupted in patients with neuronal disorders, the mechanism underlying the pathogenesis is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases. PMID:25519132

  2. TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation.

    PubMed Central

    Taylor, J P; Pomerantz, R; Bagasra, O; Chowdhury, M; Rappaport, J; Khalili, K; Amini, S

    1992-01-01

    The Tat protein of human immunodeficiency virus type 1 (HIV-1) is essential for productive infection and is a potential target for antiviral therapy. Tat, a potent activator of HIV-1 gene expression, serves to greatly increase the rate of transcription directed by the viral promoter. This induction, which seems to be an important component in the progression of acquired immune deficiency syndrome (AIDS), may be due to increased transcriptional initiation, increased transcriptional elongation, or a combination of these processes. Much attention has been focused on the interaction of Tat with a specific RNA target termed TAR (transactivation responsive) which is present in the leader sequence of all HIV-1 mRNAs. This interaction is believed to be an important component of the mechanism of transactivation. In this report we demonstrate that in certain CNS-derived cells Tat is capable of activating HIV-1 through a TAR-independent pathway. A Tat-responsive element is found upstream within the viral promoter that in glial-derived cell lines allows transactivation in the absence of TAR. Deletion mapping and hybrid promoter constructs demonstrate that the newly identified Tat-responsive element corresponds to a sequence within the viral long terminal repeat (LTR) previously identified as the HIV-1 enhancer, or NF-kappa B domain. DNA band-shift analysis reveals NF-kappa B binding activity in glial cells that differs from that present in T lymphoid cells. Further, we observe that TAR-deleted mutants of HIV-1 demonstrate normal late gene expression in glial cells as evidenced by syncytia formation and production of viral p24 antigen.(ABSTRACT TRUNCATED AT 250 WORDS) Images PMID:1505523

  3. slc7a6os Gene Plays a Critical Role in Defined Areas of the Developing CNS in Zebrafish

    PubMed Central

    Benini, Anna; Cignarella, Francesca; Calvarini, Laura; Mantovanelli, Silvia; Giacopuzzi, Edoardo; Zizioli, Daniela; Borsani, Giuseppe

    2015-01-01

    The aim of this study is to shed light on the functional role of slc7a6os, a gene highly conserved in vertebrates. The Danio rerio slc7a6os gene encodes a protein of 326 amino acids with 46% identity to human SLC7A6OS and 14% to Saccharomyces cerevisiae polypeptide Iwr1. Yeast Iwr1 specifically binds RNA pol II, interacts with the basal transcription machinery and regulates the transcription of specific genes. In this study we investigated for the first time the biological role of SLC7A6OS in vertebrates. Zebrafish slc7a6os is a maternal gene that is expressed throughout development, with a prevalent localization in the developing central nervous system (CNS). The gene is also expressed, although at different levels, in various tissues of the adult fish. To determine the functional role of slc7a6os during zebrafish development, we knocked-down the gene by injecting a splice-blocking morpholino. At 24 hpf morphants show morphological defects in the CNS, particularly the interface between hindbrain and midbrain is not well-defined. At 28 hpf the morpholino injected embryos present an altered somite morphology and appear partially or completely immotile. At this stage the midbrain, hindbrain and cerebellum are compromised and not well defined compared with control embryos. The observed alterations persist at later developmental stages. Consistently, the expression pattern of two markers specifically expressed in the developing CNS, pax2a and neurod, is significantly altered in morphants. The co-injection of embryos with synthetic slc7a6os mRNA, rescues the morphant phenotype and restores the wild type expression pattern of pax2a and neurod. Our data suggest that slc7a6os might play a critical role in defined areas of the developing CNS in vertebrates, probably by regulating the expression of key genes. PMID:25803583

  4. Advances in microRNA experimental approaches to study physiological regulation of gene products implicated in CNS disorders

    PubMed Central

    Long, Justin M.; Lahiri, Debomoy K.

    2013-01-01

    The central nervous system (CNS) is a remarkably complex organ system, requiring an equally complex network of molecular pathways controlling the multitude of diverse, cellular activities. Gene expression is a critical node at which regulatory control of molecular networks is implemented. As such, elucidating the various mechanisms employed in the physiological regulation of gene expression in the CNS is important both for establishing a reference for comparison to the diseased state and for expanding the set of validated drug targets available for disease intervention. MicroRNAs (miRNAs) are an abundant class of small RNA that mediates potent inhibitory effects on global gene expression. Recent advances have been made in methods employed to study the contribution of these miRNAs to gene expression. Here we review these latest advances and present a methodological workflow from the perspective of an investigator studying the physiological regulation of a gene of interest. We discuss methods for identifying putative miRNA target sites in a transcript of interest, strategies for validating predicted target sites, assays for detecting miRNA expression, and approaches for disrupting endogenous miRNA function. We consider both advantages and limitations, highlighting certain caveats that inform the suitability of a given method for a specific application. Through careful implementation of the appropriate methodologies discussed herein, we are optimistic that important discoveries related to miRNA participation in CNS physiology and dysfunction are on the horizon. PMID:22245616

  5. Gene expression profiles uncover individual identities of gnathal neuroblasts and serial homologies in the embryonic CNS of Drosophila

    PubMed Central

    Urbach, Rolf; Jussen, David; Technau, Gerhard M.

    2016-01-01

    The numbers and types of progeny cells generated by neural stem cells in the developing CNS are adapted to its region-specific functional requirements. In Drosophila, segmental units of the CNS develop from well-defined patterns of neuroblasts. Here we constructed comprehensive neuroblast maps for the three gnathal head segments. Based on the spatiotemporal pattern of neuroblast formation and the expression profiles of 46 marker genes (41 transcription factors), each neuroblast can be uniquely identified. Compared with the thoracic ground state, neuroblast numbers are progressively reduced in labial, maxillary and mandibular segments due to smaller sizes of neuroectodermal anlagen and, partially, to suppression of neuroblast formation and induction of programmed cell death by the Hox gene Deformed. Neuroblast patterns are further influenced by segmental modifications in dorsoventral and proneural gene expression. With the previously published neuroblast maps and those presented here for the gnathal region, all neuroectodermal neuroblasts building the CNS of the fly (ventral nerve cord and brain, except optic lobes) are now individually identified (in total 2×567 neuroblasts). This allows, for the first time, a comparison of the characteristics of segmental populations of stem cells and to screen for serially homologous neuroblasts throughout the CNS. We show that approximately half of the deutocerebral and all of the tritocerebral (posterior brain) and gnathal neuroblasts, but none of the protocerebral (anterior brain) neuroblasts, display serial homology to neuroblasts in thoracic/abdominal neuromeres. Modifications in the molecular signature of serially homologous neuroblasts are likely to determine the segment-specific characteristics of their lineages. PMID:27095493

  6. Evaluation of cell proliferation, apoptosis, and dna-repair genes as potential biomarkers for ethanol-induced cns alterations

    PubMed Central

    2012-01-01

    Background Alcohol use disorders (AUDs) lead to alterations in central nervous system (CNS) architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs) produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure. Results Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs) of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP) assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1) was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5) showed a highly significant correlation with AUD-induced decreases in the volume of the left parietal supramarginal

  7. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan.

    PubMed

    Weismann, Cara M; Ferreira, Jennifer; Keeler, Allison M; Su, Qin; Qui, Linghua; Shaffer, Scott A; Xu, Zuoshang; Gao, Guangping; Sena-Esteves, Miguel

    2015-08-01

    GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease where GLB1 gene mutations result in a reduction or absence of lysosomal acid β-galactosidase (βgal) activity. βgal deficiency leads to accumulation of GM1-ganglioside in the central nervous system (CNS). GM1 is characterized by progressive neurological decline resulting in generalized paralysis, extreme emaciation and death. In this study, we assessed the therapeutic efficacy of an adeno-associated virus (AAV) 9-mβgal vector infused systemically in adult GM1 mice (βGal(-/-)) at 1 × 10(11) or 3 × 10(11) vector genomes (vg). Biochemical analysis of AAV9-treated GM1 mice showed high βGal activity in liver and serum. Moderate βGal levels throughout CNS resulted in a 36-76% reduction in GM1-ganglioside content in the brain and 75-86% in the spinal cord. Histological analyses of the CNS of animals treated with 3 × 10(11) vg dose revealed increased presence of βgal and clearance of lysosomal storage throughout cortex, hippocampus, brainstem and spinal cord. Storage reduction in these regions was accompanied by a marked decrease in astrogliosis. AAV9 treatment resulted in improved performance in multiple tests of motor function and behavior. Also the majority of GM1 mice in the 3 × 10(11) vg cohort retained ambulation and rearing despite reaching the humane endpoint due to weight loss. Importantly, the median survival of AAV9 treatment groups (316-576 days) was significantly increased over controls (250-264 days). This study shows that moderate widespread expression of βgal in the CNS of GM1 gangliosidosis mice is sufficient to achieve significant biochemical impact with phenotypic amelioration and extension in lifespan. PMID:25964428

  8. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan

    PubMed Central

    Weismann, Cara M.; Ferreira, Jennifer; Keeler, Allison M.; Su, Qin; Qui, Linghua; Shaffer, Scott A.; Xu, Zuoshang; Gao, Guangping; Sena-Esteves, Miguel

    2015-01-01

    GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease where GLB1 gene mutations result in a reduction or absence of lysosomal acid β-galactosidase (βgal) activity. βgal deficiency leads to accumulation of GM1-ganglioside in the central nervous system (CNS). GM1 is characterized by progressive neurological decline resulting in generalized paralysis, extreme emaciation and death. In this study, we assessed the therapeutic efficacy of an adeno-associated virus (AAV) 9-mβgal vector infused systemically in adult GM1 mice (βGal−/−) at 1 × 1011 or 3 × 1011 vector genomes (vg). Biochemical analysis of AAV9-treated GM1 mice showed high βGal activity in liver and serum. Moderate βGal levels throughout CNS resulted in a 36–76% reduction in GM1-ganglioside content in the brain and 75–86% in the spinal cord. Histological analyses of the CNS of animals treated with 3 × 1011 vg dose revealed increased presence of βgal and clearance of lysosomal storage throughout cortex, hippocampus, brainstem and spinal cord. Storage reduction in these regions was accompanied by a marked decrease in astrogliosis. AAV9 treatment resulted in improved performance in multiple tests of motor function and behavior. Also the majority of GM1 mice in the 3 × 1011 vg cohort retained ambulation and rearing despite reaching the humane endpoint due to weight loss. Importantly, the median survival of AAV9 treatment groups (316–576 days) was significantly increased over controls (250–264 days). This study shows that moderate widespread expression of βgal in the CNS of GM1 gangliosidosis mice is sufficient to achieve significant biochemical impact with phenotypic amelioration and extension in lifespan. PMID:25964428

  9. Long-range regulation by shared retinoic acid response elements modulates dynamic expression of posterior Hoxb genes in CNS development.

    PubMed

    Ahn, Youngwook; Mullan, Hillary E; Krumlauf, Robb

    2014-04-01

    Retinoic acid (RA) signaling plays an important role in determining the anterior boundary of Hox gene expression in the neural tube during embryogenesis. In particular, RA signaling is implicated in a rostral expansion of the neural expression domain of 5׳ Hoxb genes (Hoxb9-Hoxb5) in mice. However, underlying mechanisms for this gene regulation have remained elusive due to the lack of RA responsive element (RARE) in the 5׳ half of the HoxB cluster. To identify cis-regulatory elements required for the rostral expansion, we developed a recombineering technology to serially label multiple genes with different reporters in a single bacterial artificial chromosome (BAC) vector containing the mouse HoxB cluster. This allowed us to simultaneously monitor the expression of multiple genes. In contrast to plasmid-based reporters, transgenic BAC reporters faithfully recapitulated endogenous gene expression patterns of the Hoxb genes including the rostral expansion. Combined inactivation of two RAREs, DE-RARE and ENE-RARE, in the BAC completely abolished the rostral expansion of the 5׳ Hoxb genes. Knock-out of endogenous DE-RARE lead to significantly reduced expression of multiple Hoxb genes and attenuated Hox gene response to exogenous RA treatment in utero. Regulatory potential of DE-RARE was further demonstrated by its ability to anteriorize 5׳ Hoxa gene expression in the neural tube when inserted into a HoxA BAC reporter. Our data demonstrate that multiple RAREs cooperate to remotely regulate 5׳ Hoxb genes during CNS development, providing a new insight into the mechanisms for gene regulation within the Hox clusters. PMID:24525295

  10. Automated conserved non-coding sequence (CNS) discovery reveals differences in gene content and promoter evolution among grasses

    PubMed Central

    Turco, Gina; Schnable, James C.; Pedersen, Brent; Freeling, Michael

    2013-01-01

    Conserved non-coding sequences (CNS) are islands of non-coding sequence that, like protein coding exons, show less divergence in sequence between related species than functionless DNA. Several CNSs have been demonstrated experimentally to function as cis-regulatory regions. However, the specific functions of most CNSs remain unknown. Previous searches for CNS in plants have either anchored on exons and only identified nearby sequences or required years of painstaking manual annotation. Here we present an open source tool that can accurately identify CNSs between any two related species with sequenced genomes, including both those immediately adjacent to exons and distal sequences separated by >12 kb of non-coding sequence. We have used this tool to characterize new motifs, associate CNSs with additional functions, and identify previously undetected genes encoding RNA and protein in the genomes of five grass species. We provide a list of 15,363 orthologous CNSs conserved across all grasses tested. We were also able to identify regulatory sequences present in the common ancestor of grasses that have been lost in one or more extant grass lineages. Lists of orthologous gene pairs and associated CNSs are provided for reference inbred lines of arabidopsis, Japonica rice, foxtail millet, sorghum, brachypodium, and maize. PMID:23874343

  11. Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

    PubMed Central

    Hiolski, Emma M; Kendrick, Preston S; Frame, Elizabeth R; Myers, Mark S; Bammler, Theo K; Beyer, Richard P; Farin, Federico M; Wilkerson, Hui-wen; Smith, Donald R; Marcinek, David J; Lefebvre, Kathi A

    2014-01-01

    Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: 1) identify transcriptional biomarkers of exposure; and 2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly-variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences. PMID:25033243

  12. Cell-Autonomous and Non-cell-autonomous Function of Hox Genes Specify Segmental Neuroblast Identity in the Gnathal Region of the Embryonic CNS in Drosophila

    PubMed Central

    Becker, Henrike; Renner, Simone; Technau, Gerhard M.; Berger, Christian

    2016-01-01

    During central nervous system (CNS) development neural stem cells (Neuroblasts, NBs) have to acquire an identity appropriate to their location. In thoracic and abdominal segments of Drosophila, the expression pattern of Bithorax-Complex Hox genes is known to specify the segmental identity of NBs prior to their delamination from the neuroectoderm. Compared to the thoracic, ground state segmental units in the head region are derived to different degrees, and the precise mechanism of segmental specification of NBs in this region is still unclear. We identified and characterized a set of serially homologous NB-lineages in the gnathal segments and used one of them (NB6-4 lineage) as a model to investigate the mechanism conferring segment-specific identities to gnathal NBs. We show that NB6-4 is primarily determined by the cell-autonomous function of the Hox gene Deformed (Dfd). Interestingly, however, it also requires a non-cell-autonomous function of labial and Antennapedia that are expressed in adjacent anterior or posterior compartments. We identify the secreted molecule Amalgam (Ama) as a downstream target of the Antennapedia-Complex Hox genes labial, Dfd, Sex combs reduced and Antennapedia. In conjunction with its receptor Neurotactin (Nrt) and the effector kinase Abelson tyrosine kinase (Abl), Ama is necessary in parallel to the cell-autonomous Dfd pathway for the correct specification of the maxillary identity of NB6-4. Both pathways repress CyclinE (CycE) and loss of function of either of these pathways leads to a partial transformation (40%), whereas simultaneous mutation of both pathways leads to a complete transformation (100%) of NB6-4 segmental identity. Finally, we provide genetic evidences, that the Ama-Nrt-Abl-pathway regulates CycE expression by altering the function of the Hippo effector Yorkie in embryonic NBs. The disclosure of a non-cell-autonomous influence of Hox genes on neural stem cells provides new insight into the process of segmental

  13. Cell-Autonomous and Non-cell-autonomous Function of Hox Genes Specify Segmental Neuroblast Identity in the Gnathal Region of the Embryonic CNS in Drosophila.

    PubMed

    Becker, Henrike; Renner, Simone; Technau, Gerhard M; Berger, Christian

    2016-03-01

    During central nervous system (CNS) development neural stem cells (Neuroblasts, NBs) have to acquire an identity appropriate to their location. In thoracic and abdominal segments of Drosophila, the expression pattern of Bithorax-Complex Hox genes is known to specify the segmental identity of NBs prior to their delamination from the neuroectoderm. Compared to the thoracic, ground state segmental units in the head region are derived to different degrees, and the precise mechanism of segmental specification of NBs in this region is still unclear. We identified and characterized a set of serially homologous NB-lineages in the gnathal segments and used one of them (NB6-4 lineage) as a model to investigate the mechanism conferring segment-specific identities to gnathal NBs. We show that NB6-4 is primarily determined by the cell-autonomous function of the Hox gene Deformed (Dfd). Interestingly, however, it also requires a non-cell-autonomous function of labial and Antennapedia that are expressed in adjacent anterior or posterior compartments. We identify the secreted molecule Amalgam (Ama) as a downstream target of the Antennapedia-Complex Hox genes labial, Dfd, Sex combs reduced and Antennapedia. In conjunction with its receptor Neurotactin (Nrt) and the effector kinase Abelson tyrosine kinase (Abl), Ama is necessary in parallel to the cell-autonomous Dfd pathway for the correct specification of the maxillary identity of NB6-4. Both pathways repress CyclinE (CycE) and loss of function of either of these pathways leads to a partial transformation (40%), whereas simultaneous mutation of both pathways leads to a complete transformation (100%) of NB6-4 segmental identity. Finally, we provide genetic evidences, that the Ama-Nrt-Abl-pathway regulates CycE expression by altering the function of the Hippo effector Yorkie in embryonic NBs. The disclosure of a non-cell-autonomous influence of Hox genes on neural stem cells provides new insight into the process of segmental

  14. Multiplex PCR for detection of acquired carbapenemase genes.

    PubMed

    Poirel, Laurent; Walsh, Timothy R; Cuvillier, Vincent; Nordmann, Patrice

    2011-05-01

    A rapid and reliable PCR-based technique was developed for detection of genes encoding carbapenemases belonging to different classes. Primers were designed to amplify the following 11 genes: bla(IMP), bla(VIM), bla(NDM), bla(SPM), bla(AIM), bla(DIM), bla(GIM), bla(SIM)bla(KPC), bla(BIC), and bla(OXA-48). Three different multiplex reaction mixtures were defined and evaluated for the detection of all these 11 genes. Using optimized conditions, each reaction mixture allowed to identify the respective genes, with PCR giving distinct amplicon sizes corresponding to the different genes for each mixture. We reported here a rapid and reliable technique for screening all clinically relevant carbapenemase genes. PMID:21398074

  15. A recently transferred cluster of bacterial genes in Trichomonas vaginalis - lateral gene transfer and the fate of acquired genes

    PubMed Central

    2014-01-01

    Background Lateral Gene Transfer (LGT) has recently gained recognition as an important contributor to some eukaryote proteomes, but the mechanisms of acquisition and fixation in eukaryotic genomes are still uncertain. A previously defined norm for LGTs in microbial eukaryotes states that the majority are genes involved in metabolism, the LGTs are typically localized one by one, surrounded by vertically inherited genes on the chromosome, and phylogenetics shows that a broad collection of bacterial lineages have contributed to the transferome. Results A unique 34 kbp long fragment with 27 clustered genes (TvLF) of prokaryote origin was identified in the sequenced genome of the protozoan parasite Trichomonas vaginalis. Using a PCR based approach we confirmed the presence of the orthologous fragment in four additional T. vaginalis strains. Detailed sequence analyses unambiguously suggest that TvLF is the result of one single, recent LGT event. The proposed donor is a close relative to the firmicute bacterium Peptoniphilus harei. High nucleotide sequence similarity between T. vaginalis strains, as well as to P. harei, and the absence of homologs in other Trichomonas species, suggests that the transfer event took place after the radiation of the genus Trichomonas. Some genes have undergone pseudogenization and degradation, indicating that they may not be retained in the future. Functional annotations reveal that genes involved in informational processes are particularly prone to degradation. Conclusions We conclude that, although the majority of eukaryote LGTs are single gene occurrences, they may be acquired in clusters of several genes that are subsequently cleansed of evolutionarily less advantageous genes. PMID:24898731

  16. Found and Lost: The Fates of Horizontally Acquired Genes in Arthropod-Symbiotic Spiroplasma

    PubMed Central

    Lo, Wen-Sui; Gasparich, Gail E.; Kuo, Chih-Horng

    2015-01-01

    Horizontal gene transfer (HGT) is an important mechanism that contributed to biological diversity, particularly in bacteria. Through acquisition of novel genes, the recipient cell may change its ecological preference and the process could promote speciation. In this study, we determined the complete genome sequence of two Spiroplasma species for comparative analyses and inferred the putative gene gains and losses. Although most Spiroplasma species are symbionts of terrestrial insects, Spiroplasma eriocheiris has evolved to be a lethal pathogen of freshwater crustaceans. We found that approximately 7% of the genes in this genome may have originated from HGT and these genes expanded the metabolic capacity of this organism. Through comparison with the closely related Spiroplasma atrichopogonis, as well as other more divergent lineages, our results indicated that these HGT events could be traced back to the most recent common ancestor of these two species. However, most of these horizontally acquired genes have been pseudogenized in S. atrichopogonis, suggesting that they did not contribute to the fitness of this lineage that maintained the association with terrestrial insects. Thus, accumulation of small deletions that disrupted these foreign genes was not countered by natural selection. On the other hand, the long-term survival of these horizontally acquired genes in the S. eriocheiris genome hinted that they might play a role in the ecological shift of this species. Finally, the implications of these findings and the conflicts among gene content, 16S rRNA gene sequencing, and serological typing, are discussed in light of defining bacterial species. PMID:26254485

  17. A functional difference between native and horizontally acquired genes in bdelloid rotifers.

    PubMed

    Barbosa, Elton G G; Crisp, Alastair; Broadbent, Sarah E; Carrillo, Martina; Boschetti, Chiara; Tunnacliffe, Alan

    2016-09-15

    The form of RNA processing known as SL trans-splicing involves the transfer of a short conserved sequence, the spliced leader (SL), from a noncoding SL RNA to the 5' ends of mRNA molecules. SL trans-splicing occurs in several animal taxa, including bdelloid rotifers (Rotifera, Bdelloidea). One striking feature of these aquatic microinvertebrates is the large proportion of foreign genes, i.e. those acquired by horizontal gene transfer from other organisms, in their genomes. However, whether such foreign genes behave similarly to native genes has not been tested in bdelloids or any other animal. We therefore used a combination of experimental and computational methods to examine whether transcripts of foreign genes in bdelloids were SL trans-spliced, like their native counterparts. We found that many foreign transcripts contain SLs, use similar splice acceptor sequences to native genes, and are able to undergo alternative trans-splicing. However, a significantly lower proportion of foreign mRNAs contains SL sequences than native transcripts. This demonstrates a novel functional difference between foreign and native genes in bdelloids and suggests that SL trans-splicing is not essential for the expression of foreign genes, but is acquired during their domestication. PMID:27312952

  18. Long-term replacement of a mutated nonfunctional CNS gene: reversal of hypothalamic diabetes insipidus using an EIAV-based lentiviral vector expressing arginine vasopressin.

    PubMed

    Bienemann, Alison S; Martin-Rendon, Enca; Cosgrave, Anna S; Glover, Colin P J; Wong, Liang-Fong; Kingsman, Susan M; Mitrophanous, Kyriacos A; Mazarakis, Nicholas D; Uney, James B

    2003-05-01

    Due to the complexity of brain function and the difficulty in monitoring alterations in neuronal gene expression, the potential of lentiviral gene therapy vectors to treat disorders of the CNS has been difficult to fully assess. In this study, we have assessed the utility of a third-generation equine infectious anemia virus (EIAV) in the Brattleboro rat model of diabetes insipidus, in which a mutation in the arginine vasopressin (AVP) gene results in the production of nonfunctional mutant AVP precursor protein. Importantly, by using this model it is possible to monitor the success of the gene therapy treatment by noninvasive assays. Injection of an EIAV-CMV-AVP vector into the supraoptic nuclei of the hypothalamus resulted in expression of functional AVP peptide in magnocellular neurons. This was accompanied by a 100% recovery in water homeostasis as assessed by daily water intake, urine production, and urine osmolality lasting for a 1-year measurement period. These data show that a single gene defect leading to a neurological disorder can be corrected with a lentiviral-based strategy. This study highlights the potential of using viral gene therapy for the long-term treatment of disorders of the CNS. PMID:12718901

  19. Cell-type-specific Jumonji histone demethylase gene expression in the healthy rat CNS: detection by a novel flow cytometry method

    PubMed Central

    Smith, Stephanie M.C.; Kimyon, Rebecca S.; Watters, Jyoti J.

    2014-01-01

    Our understanding of how histone demethylation contributes to the regulation of basal gene expression in the brain is largely unknown in any injury model, and especially in the healthy adult brain. Although Jumonji genes are often regulated transcriptionally, cell-specific gene expression of Jumonji histone demethylases in the brain remains poorly understood. Thus, in the present study we profiled the mRNA levels of 26 Jumonji genes in microglia (CD11b+), neurons (NeuN+) and astrocytes (GFAP+) from the healthy adult rat brain. We optimized a method combining a mZBF (modified zinc-based fixative) and FCM (flow cytometry) to simultaneously sort cells from non-transgenic animals. We evaluated cell-surface, intracellular and nuclear proteins, including histones, as well as messenger- and micro-RNAs in different cell types simultaneously from a single-sorted sample. We found that 12 Jumonji genes were differentially expressed between adult microglia, neurons and astrocytes. While JMJD2D was neuron-restricted, PHF8 and JMJD1C were expressed in all three cell types although the expression was highest in neurons. JMJD3 and JMJD5 were expressed in all cell types, but were highly enriched in microglia; astrocytes had the lowest expression of UTX and JHDM1D. Levels of global H3K27 (H3 lysine 27) methylation varied among cell types and appeared to be lowest in microglia, indicating that differences in basal gene expression of specific Jumonji histone demethylases may contribute to cell-specific gene expression in the CNS (central nervous system). This multiparametric technique will be valuable for simultaneously assaying chromatin modifications and gene regulation in the adult CNS. PMID:24735454

  20. Hsp27 gene in Drosophila ananassae subgroup was split by a recently acquired intron.

    PubMed

    Zhang, Li; Kang, Han; Jin, Shan; Zeng, Qing Tao; Yang, Yong

    2016-06-01

    In Drosophila, heat shock protein 27 (Hsp27) is a critical single-copy intron-free nuclear gene involved in the defense response against fungi and bacteria, and is a regulator of adult lifespan. In the present study, 33 homologous Hsp27 nucleotide sequences from different Drosophila species were amplified by PCR and reverse transcription PCR, and the phylogenetic relationships were analysed using neighbour-joining, maximum-likelihood and Bayesian methods. The phylogenetic topologies from analysis with different algorithms were similar, suggesting that the Hsp27 gene was split by a recently acquired intron during the evolution of the Drosophila ananassae subgroup. PMID:27350667

  1. Bacterial α2-macroglobulins: colonization factors acquired by horizontal gene transfer from the metazoan genome?

    PubMed Central

    Budd, Aidan; Blandin, Stephanie; Levashina, Elena A; Gibson, Toby J

    2004-01-01

    Background Invasive bacteria are known to have captured and adapted eukaryotic host genes. They also readily acquire colonizing genes from other bacteria by horizontal gene transfer. Closely related species such as Helicobacter pylori and Helicobacter hepaticus, which exploit different host tissues, share almost none of their colonization genes. The protease inhibitor α2-macroglobulin provides a major metazoan defense against invasive bacteria, trapping attacking proteases required by parasites for successful invasion. Results Database searches with metazoan α2-macroglobulin sequences revealed homologous sequences in bacterial proteomes. The bacterial α2-macroglobulin phylogenetic distribution is patchy and violates the vertical descent model. Bacterial α2-macroglobulin genes are found in diverse clades, including purple bacteria (proteobacteria), fusobacteria, spirochetes, bacteroidetes, deinococcids, cyanobacteria, planctomycetes and thermotogae. Most bacterial species with bacterial α2-macroglobulin genes exploit higher eukaryotes (multicellular plants and animals) as hosts. Both pathogenically invasive and saprophytically colonizing species possess bacterial α2-macroglobulins, indicating that bacterial α2-macroglobulin is a colonization rather than a virulence factor. Conclusions Metazoan α2-macroglobulins inhibit proteases of pathogens. The bacterial homologs may function in reverse to block host antimicrobial defenses. α2-macroglobulin was probably acquired one or more times from metazoan hosts and has then spread widely through other colonizing bacterial species by more than 10 independent horizontal gene transfers. yfhM-like bacterial α2-macroglobulin genes are often found tightly linked with pbpC, encoding an atypical peptidoglycan transglycosylase, PBP1C, that does not function in vegetative peptidoglycan synthesis. We suggest that YfhM and PBP1C are coupled together as a periplasmic defense and repair system. Bacterial α2-macroglobulins might

  2. Comparative Pathogenomics Reveals Horizontally Acquired Novel Virulence Genes in Fungi Infecting Cereal Hosts

    PubMed Central

    Gardiner, Donald M.; McDonald, Megan C.; Covarelli, Lorenzo; Solomon, Peter S.; Rusu, Anca G.; Marshall, Mhairi; Kazan, Kemal; Chakraborty, Sukumar; McDonald, Bruce A.; Manners, John M.

    2012-01-01

    Comparative analyses of pathogen genomes provide new insights into how pathogens have evolved common and divergent virulence strategies to invade related plant species. Fusarium crown and root rots are important diseases of wheat and barley world-wide. In Australia, these diseases are primarily caused by the fungal pathogen Fusarium pseudograminearum. Comparative genomic analyses showed that the F. pseudograminearum genome encodes proteins that are present in other fungal pathogens of cereals but absent in non-cereal pathogens. In some cases, these cereal pathogen specific genes were also found in bacteria associated with plants. Phylogenetic analysis of selected F. pseudograminearum genes supported the hypothesis of horizontal gene transfer into diverse cereal pathogens. Two horizontally acquired genes with no previously known role in fungal pathogenesis were studied functionally via gene knockout methods and shown to significantly affect virulence of F. pseudograminearum on the cereal hosts wheat and barley. Our results indicate using comparative genomics to identify genes specific to pathogens of related hosts reveals novel virulence genes and illustrates the importance of horizontal gene transfer in the evolution of plant infecting fungal pathogens. PMID:23028337

  3. STARs in the CNS.

    PubMed

    Ehrmann, Ingrid; Fort, Philippe; Elliott, David J

    2016-08-15

    STAR (signal transduction and activation of RNA) proteins regulate splicing of target genes that have roles in neural connectivity, survival and myelination in the vertebrate nervous system. These regulated splicing targets include mRNAs such as the Neurexins (Nrxn), SMN2 (survival of motor neuron) and MAG (myelin-associated glycoprotein). Recent work has made it possible to identify and validate STAR protein splicing targets in vivo by using genetically modified mouse models. In this review, we will discuss the importance of STAR protein splicing targets in the CNS (central nervous system). PMID:27528753

  4. Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe-affected non-human primates by intracerebral lentiviral gene therapy.

    PubMed

    Meneghini, Vasco; Lattanzi, Annalisa; Tiradani, Luigi; Bravo, Gabriele; Morena, Francesco; Sanvito, Francesca; Calabria, Andrea; Bringas, John; Fisher-Perkins, Jeanne M; Dufour, Jason P; Baker, Kate C; Doglioni, Claudio; Montini, Eugenio; Bunnell, Bruce A; Bankiewicz, Krystof; Martino, Sabata; Naldini, Luigi; Gritti, Angela

    2016-01-01

    Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD or Krabbe disease) are severe neurodegenerative lysosomal storage diseases (LSD) caused by arylsulfatase A (ARSA) and galactosylceramidase (GALC) deficiency, respectively. Our previous studies established lentiviral gene therapy (GT) as a rapid and effective intervention to provide pervasive supply of therapeutic lysosomal enzymes in CNS tissues of MLD and GLD mice. Here, we investigated whether this strategy is similarly effective in juvenile non-human primates (NHP). To provide proof of principle for tolerability and biological efficacy of the strategy, we established a comprehensive study in normal NHP delivering a clinically relevant lentiviral vector encoding for the human ARSA transgene. Then, we injected a lentiviral vector coding for the human GALC transgene in Krabbe-affected rhesus macaques, evaluating for the first time the therapeutic potential of lentiviral GT in this unique LSD model. We showed favorable safety profile and consistent pattern of LV transduction and enzyme biodistribution in the two models, supporting the robustness of the proposed GT platform. We documented moderate inflammation at the injection sites, mild immune response to vector particles in few treated animals, no indication of immune response against transgenic products, and no molecular evidence of insertional genotoxicity. Efficient gene transfer in neurons, astrocytes, and oligodendrocytes close to the injection sites resulted in robust production and extensive spreading of transgenic enzymes in the whole CNS and in CSF, leading to supraphysiological ARSA activity in normal NHP and close to physiological GALC activity in the Krabbe NHP, in which biological efficacy was associated with preliminary indication of therapeutic benefit. These results support the rationale for the clinical translation of intracerebral lentiviral GT to address CNS pathology in MLD, GLD, and other neurodegenerative LSD. PMID

  5. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates.

    PubMed

    Gray, S J; Nagabhushan Kalburgi, S; McCown, T J; Jude Samulski, R

    2013-04-01

    Injection of adeno-associated virus (AAV) into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals. In contrast to studies with other serotypes (AAV2, AAV4 and AAV5) in rodents, we report that a naturally occurring capsid (AAV9) and rationally engineered capsid (AAV2.5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP). Using either vector at a dose of ∼2 × 10(12) vector genome (vg) per 3-6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the central nervous system (CNS). AAV9 in particular displayed efficient transduction of spinal cord motor neurons. The peripheral organ biodistribution was highly reduced compared with intravascular delivery, and the presence of circulating anti-AAV-neutralizing antibodies up to a 1:128 titer had no inhibitory effect on CNS gene transfer. Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases. PMID:23303281

  6. Selective pressure against horizontally acquired prokaryotic genes as a driving force of plastid evolution.

    PubMed

    Llorente, Briardo; de Souza, Flavio S J; Soto, Gabriela; Meyer, Cristian; Alonso, Guillermo D; Flawiá, Mirtha M; Bravo-Almonacid, Fernando; Ayub, Nicolás D; Rodríguez-Concepción, Manuel

    2016-01-01

    The plastid organelle comprises a high proportion of nucleus-encoded proteins that were acquired from different prokaryotic donors via independent horizontal gene transfers following its primary endosymbiotic origin. What forces drove the targeting of these alien proteins to the plastid remains an unresolved evolutionary question. To better understand this process we screened for suitable candidate proteins to recapitulate their prokaryote-to-eukaryote transition. Here we identify the ancient horizontal transfer of a bacterial polyphenol oxidase (PPO) gene to the nuclear genome of an early land plant ancestor and infer the possible mechanism behind the plastidial localization of the encoded enzyme. Arabidopsis plants expressing PPO versions either lacking or harbouring a plastid-targeting signal allowed examining fitness consequences associated with its subcellular localization. Markedly, a deleterious effect on plant growth was highly correlated with PPO activity only when producing the non-targeted enzyme, suggesting that selection favoured the fixation of plastid-targeted protein versions. Our results reveal a possible evolutionary mechanism of how selection against heterologous genes encoding cytosolic proteins contributed in incrementing plastid proteome complexity from non-endosymbiotic gene sources, a process that may also impact mitochondrial evolution. PMID:26750147

  7. Selective pressure against horizontally acquired prokaryotic genes as a driving force of plastid evolution

    PubMed Central

    Llorente, Briardo; de Souza, Flavio S. J.; Soto, Gabriela; Meyer, Cristian; Alonso, Guillermo D.; Flawiá, Mirtha M.; Bravo-Almonacid, Fernando; Ayub, Nicolás D.; Rodríguez-Concepción, Manuel

    2016-01-01

    The plastid organelle comprises a high proportion of nucleus-encoded proteins that were acquired from different prokaryotic donors via independent horizontal gene transfers following its primary endosymbiotic origin. What forces drove the targeting of these alien proteins to the plastid remains an unresolved evolutionary question. To better understand this process we screened for suitable candidate proteins to recapitulate their prokaryote-to-eukaryote transition. Here we identify the ancient horizontal transfer of a bacterial polyphenol oxidase (PPO) gene to the nuclear genome of an early land plant ancestor and infer the possible mechanism behind the plastidial localization of the encoded enzyme. Arabidopsis plants expressing PPO versions either lacking or harbouring a plastid-targeting signal allowed examining fitness consequences associated with its subcellular localization. Markedly, a deleterious effect on plant growth was highly correlated with PPO activity only when producing the non-targeted enzyme, suggesting that selection favoured the fixation of plastid-targeted protein versions. Our results reveal a possible evolutionary mechanism of how selection against heterologous genes encoding cytosolic proteins contributed in incrementing plastid proteome complexity from non-endosymbiotic gene sources, a process that may also impact mitochondrial evolution. PMID:26750147

  8. The Zebrafish Homologue of the Human DYT1 Dystonia Gene Is Widely Expressed in CNS Neurons but Non-Essential for Early Motor System Development

    PubMed Central

    Sager, Jonathan J.; Torres, Gonzalo E.; Burton, Edward A.

    2012-01-01

    DYT1 dystonia is caused by mutation of the TOR1A gene, resulting in the loss of a single glutamic acid residue near the carboxyl terminal of TorsinA. The neuronal functions perturbed by TorsinA[ΔE] are a major unresolved issue in understanding the pathophysiology of dystonia, presenting a critical roadblock to developing effective treatments. We identified and characterized the zebrafish homologue of TOR1A, as a first step towards elucidating the functions of TorsinA in neurons, in vivo, using the genetically-manipulable zebrafish model. The zebrafish genome was found to contain a single alternatively-spliced tor1 gene, derived from a common ancestral locus shared with the dual TOR1A and TOR1B paralogues found in tertrapods. tor1 was expressed ubiquitously during early embryonic development and in multiple adult tissues, including the CNS. The 2.1 kb tor1 mRNA encodes Torsin1, which is 59% identical and 78% homologous to human TorsinA. Torsin1 was expressed as major 45 kDa and minor 47 kDa glycoproteins, within the cytoplasm of neurons and neuropil throughout the CNS. Similar to previous findings relating to human TorsinA, mutations of the ATP hydrolysis domain of Torsin1 resulted in relocalization of the protein in cultured cells from the endoplasmic reticulum to the nuclear envelope. Zebrafish embryos lacking tor1 during early development did not show impaired viability, overt morphological abnormalities, alterations in motor behavior, or developmental defects in the dopaminergic system. Torsin1 is thus non-essential for early development of the motor system, suggesting that important CNS functions may occur later in development, consistent with the critical time window in late childhood when dystonia symptoms usually emerge in DYT1 patients. The similarities between Torsin1 and human TorsinA in domain organization, expression pattern, and cellular localization suggest that the zebrafish will provide a useful model to understand the neuronal functions of Torsins

  9. ToxR Antagonizes H-NS Regulation of Horizontally Acquired Genes to Drive Host Colonization.

    PubMed

    Kazi, Misha I; Conrado, Aaron R; Mey, Alexandra R; Payne, Shelley M; Davies, Bryan W

    2016-04-01

    The virulence regulator ToxR initiates and coordinates gene expression needed by Vibrio cholerae to colonize the small intestine and cause disease. Despite its prominence in V. cholerae virulence, our understanding of the direct ToxR regulon is limited to four genes: toxT, ompT, ompU and ctxA. Here, we determine ToxR's genome-wide DNA-binding profile and demonstrate that ToxR is a global regulator of both progenitor genome-encoded genes and horizontally acquired islands that encode V. cholerae's major virulence factors and define pandemic lineages. We show that ToxR shares more than a third of its regulon with the histone-like nucleoid structuring protein H-NS, and antagonizes H-NS binding at shared binding locations. Importantly, we demonstrate that this regulatory interaction is the critical function of ToxR in V. cholerae colonization and biofilm formation. In the absence of H-NS, ToxR is no longer required for V. cholerae to colonize the infant mouse intestine or for robust biofilm formation. We further illustrate a dramatic difference in regulatory scope between ToxR and other prominent virulence regulators, despite similar predicted requirements for DNA binding. Our results suggest that factors in addition to primary DNA structure influence the ability of ToxR to recognize its target promoters. PMID:27070545

  10. ToxR Antagonizes H-NS Regulation of Horizontally Acquired Genes to Drive Host Colonization

    PubMed Central

    Kazi, Misha I.; Conrado, Aaron R.; Mey, Alexandra R.; Payne, Shelley M.; Davies, Bryan W.

    2016-01-01

    The virulence regulator ToxR initiates and coordinates gene expression needed by Vibrio cholerae to colonize the small intestine and cause disease. Despite its prominence in V. cholerae virulence, our understanding of the direct ToxR regulon is limited to four genes: toxT, ompT, ompU and ctxA. Here, we determine ToxR’s genome-wide DNA-binding profile and demonstrate that ToxR is a global regulator of both progenitor genome-encoded genes and horizontally acquired islands that encode V. cholerae’s major virulence factors and define pandemic lineages. We show that ToxR shares more than a third of its regulon with the histone-like nucleoid structuring protein H-NS, and antagonizes H-NS binding at shared binding locations. Importantly, we demonstrate that this regulatory interaction is the critical function of ToxR in V. cholerae colonization and biofilm formation. In the absence of H-NS, ToxR is no longer required for V. cholerae to colonize the infant mouse intestine or for robust biofilm formation. We further illustrate a dramatic difference in regulatory scope between ToxR and other prominent virulence regulators, despite similar predicted requirements for DNA binding. Our results suggest that factors in addition to primary DNA structure influence the ability of ToxR to recognize its target promoters. PMID:27070545

  11. Sequencing of the Reannotated LMNB2 Gene Reveals Novel Mutations in Patients with Acquired Partial Lipodystrophy

    PubMed Central

    Hegele, Robert A.; Cao, Henian; Liu, Dora M.; Costain, Gary A.; Charlton-Menys, Valentine; Rodger, N. Wilson; Durrington, Paul N.

    2006-01-01

    The etiology of acquired partial lipodystrophy (APL, also called “Barraquer-Simons syndrome”) is unknown. Genomic DNA mutations affecting the nuclear lamina protein lamin A cause inherited partial lipodystrophy but are not found in patients with APL. Because it also encodes a nuclear lamina protein (lamin B2) and its genomic structure was recently reannotated, we sequenced LMNB2 as a candidate gene in nine white patients with APL. In four patients, we found three new rare mutations in LMNB2: intron 1 −6G→T, exon 5 c.643G→A (p.R215Q; in two patients), and exon 8 c.1218G→A (p.A407T). The combined frequency of these mutations was 0.222 in the patients with APL, compared with 0.0018 in a multiethnic control sample of 1,100 subjects (P=2.1×10-7) and 0.0045 in a sample of 330 white controls (P=1.2×10-5). These novel heterozygous mutations are the first reported for LMNB2, are the first reported among patients with APL, and indicate how sequencing of a reannotated candidate gene can reveal new disease-associated mutations. PMID:16826530

  12. CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector.

    PubMed

    Murlidharan, Giridhar; Sakamoto, Kensuke; Rao, Lavanya; Corriher, Travis; Wang, Dan; Gao, Guangping; Sullivan, Patrick; Asokan, Aravind

    2016-01-01

    Gene therapy using recombinant adeno-associated viral (AAV) vectors is emerging as a promising approach to treat central nervous system disorders such as Spinal muscular atrophy, Batten, Parkinson and Alzheimer disease amongst others. A critical remaining challenge for central nervous system-targeted gene therapy, silencing or gene editing is to limit potential vector dose-related toxicity in off-target cells and organs. Here, we characterize a lab-derived AAV chimeric (AAV2g9), which displays favorable central nervous system attributes derived from both parental counterparts, AAV2 and AAV9. This synthetic AAV strain displays preferential, robust, and widespread neuronal transduction within the brain and decreased glial tropism. Importantly, we observed minimal systemic leakage, decreased sequestration and gene transfer in off-target organs with AAV2g9, when administered into the cerebrospinal fluid. A single intracranial injection of AAV2g9 vectors encoding guide RNAs targeting the schizophrenia risk gene MIR137 (encoding MIR137) in CRISPR/Cas9 knockin mice resulted in brain-specific gene deletion with no detectable events in the liver. This engineered AAV vector is a promising platform for treating neurological disorders through gene therapy, silencing or editing modalities. PMID:27434683

  13. TOPP in the CNS

    NASA Astrophysics Data System (ADS)

    Smart, R. L.; Lattanzi, M. G.; Jahreiss, H.; Bucciarelli, B.; Massone, G.

    2006-08-01

    Introduction: We present the Torino Observatory Parallax Program (TOPP) results for 22 candidates for the Catalog of Nearby Stars (CNS). Methods: Observations were made with the Torino OTAP 1.05m telescope over the period 1996-2001. Results: For the 22 objects examined 12 are within the CNS limit. Discussion: We discuss at length the objects out side the CNS limits which are either misclassified or objects with incorrect trigonometric parallaxes.

  14. An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis.

    PubMed

    Macauley, Shannon L; Wong, Andrew M S; Shyng, Charles; Augner, David P; Dearborn, Joshua T; Pearse, Yewande; Roberts, Marie S; Fowler, Stephen C; Cooper, Jonathan D; Watterson, D Martin; Sands, Mark S

    2014-09-24

    Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative lysosomal storage disease (LSD) caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). Studies in Ppt1(-/-) mice demonstrate that glial activation is central to the pathogenesis of INCL. Astrocyte activation precedes neuronal loss, while cytokine upregulation associated with microglial reactivity occurs before and concurrent with neurodegeneration. Therefore, we hypothesized that cytokine cascades associated with neuroinflammation are important therapeutic targets for the treatment of INCL. MW01-2-151SRM (MW151) is a blood-brain barrier penetrant, small-molecule anti-neuroinflammatory that attenuates glial cytokine upregulation in models of neuroinflammation such as traumatic brain injury, Alzheimer's disease, and kainic acid toxicity. Thus, we used MW151, alone and in combination with CNS-directed, AAV-mediated gene therapy, as a possible treatment for INCL. MW151 alone decreased seizure susceptibility. When combined with AAV-mediated gene therapy, treated INCL mice had increased life spans, improved motor performance, and eradication of seizures. Combination-treated INCL mice also had decreased brain atrophy, astrocytosis, and microglial activation, as well as intermediary effects on cytokine upregulation. These data suggest that MW151 can attenuate seizure susceptibility but is most effective when used in conjunction with a therapy that targets the primary genetic defect. PMID:25253854

  15. Heroin self-administration: II. CNS gene expression following withdrawal and cue-induced drug-seeking behavior.

    PubMed

    Kuntz, Kara L; Patel, Kruti M; Grigson, Patricia S; Freeman, Willard M; Vrana, Kent E

    2008-09-01

    In the accompanying paper, we described incubation of heroin-seeking behavior in rats following 14 days of abstinence. To gain an understanding of genomic changes that accompany this behavioral observation, we measured the expression of genes previously reported to respond to drugs of abuse. Specifically, after 1 or 14 days of abstinence, mRNA expression was measured for 11 genes in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) immediately following a single 90 min extinction session. Additionally, the role of contingency was examined in control rats that received yoked, response-independent heroin administration. Gene expression was quantified by real-time quantitative PCR. Expression of five genes (Arc, EGR1, EGR2, Fos, and Homer1b/c) was changed in the mPFC. EGR1 and EGR2 expression was increased following the 90 min extinction session in a contingency-specific manner and this increase persisted through the 14 days of abstinence. Fos expression was also increased after 1 and 14 days of abstinence, but at 14 days this increase was response-independent (i.e., it occurred in both the rats with a history of heroin self-administration and in the yoked controls). Arc expression increased following the extinction session only in rats with a history of heroin self-administration and only when tested following 1, but not 14, days of abstinence. Homer 1 b/c decreased after 14 days of enforced abstinence in rats that received non-contingent heroin. Expression of only a single gene (EGR2) was increased in the NAc. These data demonstrate that behavioral incubation is coincident with altered levels of specific transcripts and that this response is contingently-specific. Moreover, EGR1 and EGR2 are specifically upregulated in self-administering rats following extinction and this finding persists through 14 days of abstinence, suggesting that these genes are particularly associated with the incubation phenomenon. These latter observations of persistent changes

  16. CNS development: an overview

    NASA Technical Reports Server (NTRS)

    Nowakowski, R. S.; Hayes, N. L.

    1999-01-01

    The basic principles of the development of the central nervous system (CNS) are reviewed, and their implications for both normal and abnormal development of the brain are discussed. The goals of this review are (a) to provide a set of concepts to aid in understanding the variety of complex processes that occur during CNS development, (b) to illustrate how these concepts contribute to our knowledge of the normal anatomy of the adult brain, and (c) to provide a basis for understanding how modifications of normal developmental processes by traumatic injury, by environmental or experiential influences, or by genetic variations may lead to modifications in the resultant structure and function of the adult CNS.

  17. CNS hypomyelination in Rat Terrier dogs with congenital goiter and a mutation in the thyroid peroxidase gene.

    PubMed

    Pettigrew, R; Fyfe, J C; Gregory, B L; Lipsitz, D; Delahunta, A; Summers, B A; Shelton, G D

    2007-01-01

    Arrested physical development and neurologic abnormalities were identified in 3 of 5 Rat Terrier puppies at 9 weeks of age. Bilaterally firm symmetrical masses were palpated in the region of the thyroid glands. Low serum total (T4) and free thyroxine (FT4, by equilibrium dialysis) and markedly elevated thyroid stimulating hormone (TSH) concentrations supported the diagnosis of hypothyroidism. At necropsy, the thyroid gland was grossly enlarged and histologically exhibited severe, diffuse hyperplasia of the follicular epithelium. Gross examination of the central nervous system revealed a myelin deficiency, most evident in the corpus callosum. Regional distribution of hypomyelination was confirmed histologically, affecting the corpus callosum and, to a lesser degree, the corona radiata, the longitudinal fibers of the pons, the pyramids, and the lateral funiculi of the spinal cord. Myelin reduction was paralleled by axon reduction, suggesting that hypomyelination was a consequence of reduced axonal formation. A homozygous nonsense mutation in the thyroid peroxidase gene was identified in the affected puppies. The dam and a clinically normal litter mate were heterozygous for this mutation, confirming simple autosomal recessive inheritance of the disease trait. The same mutation, causing congenital hypothyroidism with a goiter was previously described in the Toy Fox Terrier breed. Given the ongoing practice of introducing the Toy Fox Terrier genetic background into some Rat Terrier breeding programs to obtain a smaller stature and the apparent relative incidence of the disorder in the 2 breeds, it is likely that this mutation crossed into the Rat Terrier breed from Toy Fox Terriers fairly recently. PMID:17197623

  18. Horizontally acquired genes in early-diverging pathogenic fungi enable the use of host nucleosides and nucleotides.

    PubMed

    Alexander, William G; Wisecaver, Jennifer H; Rokas, Antonis; Hittinger, Chris Todd

    2016-04-12

    Horizontal gene transfer (HGT) among bacteria, archaea, and viruses is widespread, but the extent of transfers from these lineages into eukaryotic organisms is contentious. Here we systematically identify hundreds of genes that were likely acquired horizontally from a variety of sources by the early-diverging fungal phyla Microsporidia and Cryptomycota. Interestingly, the Microsporidia have acquired via HGT several genes involved in nucleic acid synthesis and salvage, such as those encoding thymidine kinase (TK), cytidylate kinase, and purine nucleotide phosphorylase. We show that these HGT-derived nucleic acid synthesis genes tend to function at the interface between the metabolic networks of the host and pathogen. Thus, these genes likely play vital roles in diversifying the useable nucleic acid components available to the intracellular parasite, often through the direct capture of resources from the host. Using an in vivo viability assay, we also demonstrate that one of these genes, TK, encodes an enzyme that is capable of activating known prodrugs to their active form, which suggests a possible treatment route for microsporidiosis. We further argue that interfacial genes with well-understood activities, especially those horizontally transferred from bacteria or viruses, could provide medical treatments for microsporidian infections. PMID:27035945

  19. ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons.

    PubMed

    May, Melanie; Hwang, Kyu-Seok; Miles, Judith; Williams, Charlie; Niranjan, Tejasvi; Kahler, Stephen G; Chiurazzi, Pietro; Steindl, Katharina; Van Der Spek, Peter J; Swagemakers, Sigrid; Mueller, Jennifer; Stefl, Shannon; Alexov, Emil; Ryu, Jeong-Im; Choi, Jung-Hwa; Kim, Hyun-Taek; Tarpey, Patrick; Neri, Giovanni; Holloway, Lynda; Skinner, Cindy; Stevenson, Roger E; Dorsky, Richard I; Wang, Tao; Schwartz, Charles E; Kim, Cheol-Hee

    2015-09-01

    Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID re-sequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specific markers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injected with human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity of many brain and spinal circuits. PMID:26056227

  20. ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

    PubMed Central

    May, Melanie; Hwang, Kyu-Seok; Miles, Judith; Williams, Charlie; Niranjan, Tejasvi; Kahler, Stephen G.; Chiurazzi, Pietro; Steindl, Katharina; Van Der Spek, Peter J.; Swagemakers, Sigrid; Mueller, Jennifer; Stefl, Shannon; Alexov, Emil; Ryu, Jeong-Im; Choi, Jung-Hwa; Kim, Hyun-Taek; Tarpey, Patrick; Neri, Giovanni; Holloway, Lynda; Skinner, Cindy; Stevenson, Roger E.; Dorsky, Richard I.; Wang, Tao; Schwartz, Charles E.; Kim, Cheol-Hee

    2015-01-01

    Miles–Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID re-sequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specific markers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injected with human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity of many brain and spinal circuits. PMID:26056227

  1. Staging Primary CNS Lymphoma

    MedlinePlus

    ... large vein near the heart. Having a weakened immune system may increase the risk of developing primary CNS ... immunodeficiency syndrome (AIDS) or other disorders of the immune system or who have had a kidney transplant . For ...

  2. Ionotropic Glutamate Receptors & CNS Disorders

    PubMed Central

    Bowie, Derek

    2008-01-01

    Disorders of the central nervous system (CNS) are complex disease states that represent a major challenge for modern medicine. Although etiology is often unknown, it is established that multiple factors such as defects in genetics and/or epigenetics, the environment as well as imbalance in neurotransmitter receptor systems are all at play in determining an individual’s susceptibility to disease. Gene therapy is currently not available and therefore, most conditions are treated with pharmacological agents that modify neurotransmitter receptor signaling. Here, I provide a review of ionotropic glutamate receptors (iGluRs) and the roles they fulfill in numerous CNS disorders. Specifically, I argue that our understanding of iGluRs has reached a critical turning point to permit, for the first time, a comprehensive re-evaluation of their role in the cause of disease. I illustrate this by highlighting how defects in AMPA receptor trafficking are important to Fragile X mental retardation and ectopic expression of kainate (KA) receptor synapses contributes to the pathology of temporal lobe epilepsy. Finally, I discuss how parallel advances in studies of other neurotransmitter systems may allow pharmacologists to work towards a cure for many CNS disorders rather than developing drugs to treat their symptoms. PMID:18537642

  3. Multiple horizontally acquired genes from fungal and prokaryotic donors encode cellulolytic enzymes in the bdelloid rotifer Adineta ricciae.

    PubMed

    Szydlowski, L; Boschetti, C; Crisp, A; Barbosa, E G G; Tunnacliffe, A

    2015-07-25

    The bdelloid rotifer, Adineta ricciae, an anhydrobiotic microinvertebrate, exhibits a high rate of horizontal gene transfer (HGT), with as much as 10% of its transcriptome being of foreign origin. Approximately 80% of these foreign transcripts are involved in metabolic processes, and therefore bdelloids represent a useful model for assessing the contribution of HGT to biochemical diversity. To validate this concept, we focused on cellulose digestion, an unusual activity in animals, which is represented by at least 16 genes encoding cellulolytic enzymes in A. ricciae. These genes have been acquired from a variety of different donor organisms among the bacteria and fungi, demonstrating that bdelloids use diverse genetic resources to construct a novel biochemical pathway. A variable complement of the cellulolytic gene set was found in five other bdelloid species, indicating a dynamic process of gene acquisition, duplication and loss during bdelloid evolution. For example, in A. ricciae, gene duplications have led to the formation of three copies of a gene encoding a GH45 family glycoside hydrolase, at least one of which encodes a functional enzyme; all three of these gene copies are present in a close relative, Adineta vaga, but only one copy was found in each of four Rotaria species. Furthermore, analysis of expression levels of the cellulolytic genes suggests that a bacterial-origin cellobiase is upregulated upon desiccation. In summary, bdelloid rotifers have apparently developed cellulolytic functions by the acquisition and domestication of multiple foreign genes. PMID:25863176

  4. Identification of novel therapeutic target genes in acquired lapatinib-resistant breast cancer by integrative meta-analysis.

    PubMed

    Lee, Young Seok; Hwang, Sun Goo; Kim, Jin Ki; Park, Tae Hwan; Kim, Young Rae; Myeong, Ho Sung; Choi, Jong Duck; Kwon, Kang; Jang, Cheol Seong; Ro, Young Tae; Noh, Yun Hee; Kim, Sung Young

    2016-02-01

    Acquired resistance to lapatinib is a highly problematic clinical barrier that has to be overcome for a successful cancer treatment. Despite efforts to determine the mechanisms underlying acquired lapatinib resistance (ALR), no definitive genetic factors have been reported to be solely responsible for the acquired resistance in breast cancer. Therefore, we performed a cross-platform meta-analysis of three publically available microarray datasets related to breast cancer with ALR, using the R-based RankProd package. From the meta-analysis, we were able to identify a total of 990 differentially expressed genes (DEGs, 406 upregulated, 584 downregulated) that are potentially associated with ALR. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs showed that "response to organic substance" and "p53 signaling pathway" may be largely involved in ALR process. Of these, many of the top 50 upregulated and downregulated DEGs were found in oncogenesis of various tumors and cancers. For the top 50 DEGs, we constructed the gene coexpression and protein-protein interaction networks from a huge database of well-known molecular interactions. By integrative analysis of two systemic networks, we condensed the total number of DEGs to six common genes (LGALS1, PRSS23, PTRF, FHL2, TOB1, and SOCS2). Furthermore, these genes were confirmed in functional module eigens obtained from the weighted gene correlation network analysis of total DEGs in the microarray datasets ("GSE16179" and "GSE52707"). Our integrative meta-analysis could provide a comprehensive perspective into complex mechanisms underlying ALR in breast cancer and a theoretical support for further chemotherapeutic studies. PMID:26361955

  5. A Complete Set of Flagellar Genes Acquired by Horizontal Transfer Coexists with the Endogenous Flagellar System in Rhodobacter sphaeroides▿ †

    PubMed Central

    Poggio, Sebastian; Abreu-Goodger, Cei; Fabela, Salvador; Osorio, Aurora; Dreyfus, Georges; Vinuesa, Pablo; Camarena, Laura

    2007-01-01

    Bacteria swim in liquid environments by means of a complex rotating structure known as the flagellum. Approximately 40 proteins are required for the assembly and functionality of this structure. Rhodobacter sphaeroides has two flagellar systems. One of these systems has been shown to be functional and is required for the synthesis of the well-characterized single subpolar flagellum, while the other was found only after the genome sequence of this bacterium was completed. In this work we found that the second flagellar system of R. sphaeroides can be expressed and produces a functional flagellum. In many bacteria with two flagellar systems, one is required for swimming, while the other allows movement in denser environments by producing a large number of flagella over the entire cell surface. In contrast, the second flagellar system of R. sphaeroides produces polar flagella that are required for swimming. Expression of the second set of flagellar genes seems to be positively regulated under anaerobic growth conditions. Phylogenic analysis suggests that the flagellar system that was initially characterized was in fact acquired by horizontal transfer from a γ-proteobacterium, while the second flagellar system contains the native genes. Interestingly, other α-proteobacteria closely related to R. sphaeroides have also acquired a set of flagellar genes similar to the set found in R. sphaeroides, suggesting that a common ancestor received this gene cluster. PMID:17293429

  6. Assessment of variability in acquired thermotolerance: potential option to study genotypic response and the relevance of stress genes.

    PubMed

    Senthil-Kumar, Muthappa; Kumar, Ganesh; Srikanthbabu, Venkatachalayya; Udayakumar, Makarla

    2007-02-01

    High-temperature stress affects all growth stages of crops and ultimately yields. This is further aggravated by other environmental stresses like intermittent drought and high light. Management options are few and hence developing intrinsically tolerant plants is essential to combat the situation. As thermotolerance is a multigenic trait, emphasis needs to be on relevant approaches to assess genetic variability in basal and acquired tolerance. This is in fact the major aspect in crop improvement programmes. The relevance of temperature induction (acclimation) response (TIR), a high throughput approach to identify thermotolerant individuals and its utility as potential screening method is described here. This is based on the concept that stress-responsive genes are expressed only during initial stages of stress (acclimation stress) and bring about requisite changes in cell metabolism for adaptation. The fact that acclimation response is ubiquitous has been demonstrated in different crop plants in our studies and by others. Significance of acclimation in acquired tolerance and thus in assessing genetic variability in thermotolerance is discussed. The limitations of present approaches to validate the relevance of specific stress genes either in transgenics or in mutants or knock downs have been analyzed and the need to characterize transformants under conditions that trigger acquired tolerance is also highlighted. This review also focuses on the potential of exploiting acclimation response approach to improve the thermotolerance of crop plants by suitable breeding strategies. PMID:17207553

  7. Acquired copy number alterations of miRNA genes in acute myeloid leukemia are uncommon

    PubMed Central

    Ramsingh, Giridharan; Jacoby, Meagan A.; Shao, Jin; De Jesus Pizzaro, Rigoberto E.; Shen, Dong; Trissal, Maria; Getz, Angela H.; Ley, Timothy J.; Walter, Matthew J.

    2013-01-01

    Altered microRNA (miRNA) expression is frequently observed in acute myelogenous leukemia (AML) and has been implicated in leukemic transformation. Whether somatic copy number alterations (CNAs) are a frequent cause of altered miRNA gene expression is largely unknown. Herein, we used comparative genomic hybridization with a custom high-resolution miRNA-centric array and/or whole-genome sequence data to identify somatic CNAs involving miRNA genes in 113 cases of AML, including 50 cases of de novo AML, 18 cases of relapsed AML, 15 cases of secondary AML following myelodysplastic syndrome, and 30 cases of therapy-related AML. We identified a total of 48 somatic miRNA gene-containing CNAs that were not identified by routine cytogenetics in 20 patients (18%). All these CNAs also included one or more protein coding genes. We identified a single case with a hemizygous deletion of MIR223, resulting in the complete loss of miR-223 expression. Three other cases of AML were identified with very low to absent miR-223 expression, an miRNA gene known to play a key role in myelopoiesis. However, in these cases, no somatic genetic alteration of MIR223 was identified, suggesting epigenetic silencing. These data show that somatic CNAs specifically targeting miRNA genes are uncommon in AML. PMID:24009227

  8. Against All Odds: Trehalose-6-Phosphate Synthase and Trehalase Genes in the Bdelloid Rotifer Adineta vaga Were Acquired by Horizontal Gene Transfer and Are Upregulated during Desiccation

    PubMed Central

    Hespeels, Boris; Li, Xiang; Flot, Jean-François; Pigneur, Lise-Marie; Malaisse, Jeremy; Da Silva, Corinne; Van Doninck, Karine

    2015-01-01

    The disaccharide sugar trehalose is essential for desiccation resistance in most metazoans that survive dryness; however, neither trehalose nor the enzymes involved in its metabolism have ever been detected in bdelloid rotifers despite their extreme resistance to desiccation. Here we screened the genome of the bdelloid rotifer Adineta vaga for genes involved in trehalose metabolism. We discovered a total of four putative trehalose-6-phosphate synthase (TPS) and seven putative trehalase (TRE) gene copies in the genome of this ameiotic organism; however, no trehalose-6-phosphate phosphatase (TPP) gene or domain was detected. The four TPS copies of A. vaga appear more closely related to plant and fungi proteins, as well as to some protists, whereas the seven TRE copies fall in bacterial clades. Therefore, A. vaga likely acquired its trehalose biosynthesis and hydrolysis genes by horizontal gene transfers. Nearly all residues important for substrate binding in the predicted TPS domains are highly conserved, supporting the hypothesis that several copies of the genes might be functional. Besides, RNAseq library screening showed that trehalase genes were highly expressed compared to TPS genes, explaining probably why trehalose had not been detected in previous studies of bdelloids. A strong overexpression of their TPS genes was observed when bdelloids enter desiccation, suggesting a possible signaling role of trehalose-6-phosphate or trehalose in this process. PMID:26161530

  9. Forced expression of PDX-1 gene makes hepatoma cells to acquire glucose-responsive insulin secretion while maintaining hepatic characteristic.

    PubMed

    Hashimoto, H; Higuchi, Y; Kawai, K

    2015-01-01

    Evidence shows that forced expression of the PDX1 gene converts hepatoma cells, mouse liver epithelial cells (MLECs) and HepaRG cells, into insulin—producing cells, β—cells, or islets of Langerhans. However, no reports have investigated the characteristics of mouse or human hepatocytes introduced with the PDX1 gene over prolonged observation periods. In this study, we immunohistologically and molecularly investigated the alternative processes induced by PDX1 gene introduction in mouse and human hepatocytes over prolonged observation periods using immunocytochemistry, immunofluorescence, polymerase chain reaction (PCR), Western blotting, and flow cytometry (FCM) analysis. Immunocytochemical and immunofluorescent observations showed that MLECs and HepaRG cells on 2 and 21 days after introduction of the PDX1 gene comprised cells double—positive for insulin and albumin. Additionally, they showed MAFA expression and glucose—responsive insulin secretion with glucokinase expression. However mouse embryonic fibroblasts introduced with PDX1—GFP could not acquire glucose—responsive insulin secretion and glucokinase expression. Subsequently, we hypothesized that the number of albumin—positive MLECs and HepaRG cells would decrease after introduction of PDX1 due to the conversion of MLECs and HepaRG cells into insulin—producing cells. However, FCM analysis indicated that the number of albumin—positive MLECs and HepaRG cells was not altered by the introduction of PDX1. We thought that MLECs and HepaRG cells introduced with the PDX1 gene could acquire a functional insulin secretory capacity without conversion to β—cells, or islets of Langerhans, and the acquisition could need glucokinase expression. PMID:25817342

  10. Comparative Genomics Suggests That the Human Pathogenic Fungus Pneumocystis jirovecii Acquired Obligate Biotrophy through Gene Loss

    PubMed Central

    Cissé, Ousmane H.; Pagni, Marco; Hauser, Philippe M.

    2014-01-01

    Pneumocystis jirovecii is a fungal parasite that colonizes specifically humans and turns into an opportunistic pathogen in immunodeficient individuals. The fungus is able to reproduce extracellularly in host lungs without eliciting massive cellular death. The molecular mechanisms that govern this process are poorly understood, in part because of the lack of an in vitro culture system for Pneumocystis spp. In this study, we explored the origin and evolution of the putative biotrophy of P. jirovecii through comparative genomics and reconstruction of ancestral gene repertoires. We used the maximum parsimony method and genomes of related fungi of the Taphrinomycotina subphylum. Our results suggest that the last common ancestor of Pneumocystis spp. lost 2,324 genes in relation to the acquisition of obligate biotrophy. These losses may result from neutral drift and affect the biosyntheses of amino acids and thiamine, the assimilation of inorganic nitrogen and sulfur, and the catabolism of purines. In addition, P. jirovecii shows a reduced panel of lytic proteases and has lost the RNA interference machinery, which might contribute to its genome plasticity. Together with other characteristics, that is, a sex life cycle within the host, the absence of massive destruction of host cells, difficult culturing, and the lack of virulence factors, these gene losses constitute a unique combination of characteristics which are hallmarks of both obligate biotrophs and animal parasites. These findings suggest that Pneumocystis spp. should be considered as the first described obligate biotrophs of animals, whose evolution has been marked by gene losses. PMID:25062922

  11. S1 nuclease analysis of alpha-globin gene expression in preleukemic patients with acquired hemoglobin H disease after transfer to mouse erythroleukemia cells.

    PubMed

    Helder, J; Deisseroth, A

    1987-04-01

    The loss of alpha-globin gene transcriptional activity rarely occurs as an acquired abnormality during the evolution of myeloproliferative disease or preleukemia. To test whether the mutation responsible for the loss of alpha-globin gene expression (hemoglobin H disease) in these patients is linked with the alpha-globin genes on chromosome 16, we transferred chromosome 16 from preleukemic patients with acquired hemoglobin H disease to mouse erythroleukemia cells and measured the transcriptional activity of the human alpha-globin genes. After transfer to mouse erythroleukemia cells, the expression of human alpha-globin genes from the peripheral blood or marrow cells of preleukemic patients with acquired hemoglobin H disease was similar to that of human alpha-globin genes transferred to mouse erythroleukemia cells from normal donors. These data showed that factor(s) in the mouse erythroleukemia cell can genetically complement the alpha-globin gene defect in these preleukemia patients with acquired hemoglobin H disease and suggest that altered expression of a gene in trans to the alpha-globin gene may be responsible for the acquisition of hemoglobin H disease in these patients. PMID:3031681

  12. CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation.

    PubMed

    Kaji, Tomohiro; Hijikata, Atsushi; Ishige, Akiko; Kitami, Toshimori; Watanabe, Takashi; Ohara, Osamu; Yanaka, Noriyuki; Okada, Mariko; Shimoda, Michiko; Taniguchi, Masaru; Takemori, Toshitada

    2016-06-01

    Memory CD4(+) T cells promote protective humoral immunity; however, how memory T cells acquire this activity remains unclear. This study demonstrates that CD4(+) T cells develop into antigen-specific memory T cells that can promote the terminal differentiation of memory B cells far more effectively than their naive T-cell counterparts. Memory T cell development requires the transcription factor B-cell lymphoma 6 (Bcl6), which is known to direct T-follicular helper (Tfh) cell differentiation. However, unlike Tfh cells, memory T cell development did not require germinal center B cells. Curiously, memory T cells that develop in the absence of cognate B cells cannot promote memory B-cell recall responses and this defect was accompanied by down-regulation of genes associated with homeostasis and activation and up-regulation of genes inhibitory for T-cell responses. Although memory T cells display phenotypic and genetic signatures distinct from Tfh cells, both had in common the expression of a group of genes associated with metabolic pathways. This gene expression profile was not shared to any great extent with naive T cells and was not influenced by the absence of cognate B cells during memory T cell development. These results suggest that memory T cell development is programmed by stepwise expression of gatekeeper genes through serial interactions with different types of antigen-presenting cells, first licensing the memory lineage pathway and subsequently facilitating the functional development of memory T cells. Finally, we identified Gdpd3 as a candidate genetic marker for memory T cells. PMID:26714588

  13. A Laterally Acquired Galactose Oxidase-Like Gene Is Required for Aerial Development during Osmotic Stress in Streptomyces coelicolor

    PubMed Central

    Liman, Recep; Facey, Paul D.; van Keulen, Geertje; Dyson, Paul J.; Del Sol, Ricardo

    2013-01-01

    Phylogenetic reconstruction revealed that most Actinobacterial orthologs of S. coelicolor SCO2837, encoding a metal-dependent galactose oxidase-like protein, are found within Streptomyces and were probably acquired by horizontal gene transfer from fungi. Disruption of SCO2837 (glxA) caused a conditional bld phenotype that could not be reversed by extracellular complementation. Studies aimed at characterising the regulation of expression of glxA showed that it is not a target for other bld genes. We provide evidence that glxA is required for osmotic adaptation, although independently from the known osmotic stress response element SigB. glxA has been predicted to be part of an operon with the transcription unit comprising the upstream cslA gene and glxA. However, both phenotypic and expression studies indicate that it is also expressed from an independent promoter region internal to cslA. GlxA displays an in situ localisation pattern similar to that one observed for CslA at hyphal tips, but localisation of the former is independent of the latter. The functional role of GlxA in relation to CslA is discussed. PMID:23326581

  14. CNS Diseases and Uveitis

    PubMed Central

    Allegri, Pia; Rissotto, Roberto; Herbort, Carl P.; Murialdo, Ugo

    2011-01-01

    A number of inflammatory, infectious, neoplastic and idiopathic disorders affect the eye and the central nervous system (CNS) concurrently or at different time frames. These conditions pose a diagnostic challenge to the clinician since they may present with similar ocular and neurological manifestations. The purpose of this review is to describe major neurological syndromes including multiple sclerosis, Vogt-Koyanagi-Harada disease, other autoimmune syndromes, and several infectious diseases which may affect the eye. This article may serve as a guide for the diagnosis and treatment of such disorders. It should be noted that these conditions have been viewed from a neurologist’s perspective thereby neurologic involvement is stressed. PMID:22454751

  15. CNS diseases and uveitis.

    PubMed

    Allegri, Pia; Rissotto, Roberto; Herbort, Carl P; Murialdo, Ugo

    2011-10-01

    A number of inflammatory, infectious, neoplastic and idiopathic disorders affect the eye and the central nervous system (CNS) concurrently or at different time frames. These conditions pose a diagnostic challenge to the clinician since they may present with similar ocular and neurological manifestations. The purpose of this review is to describe major neurological syndromes including multiple sclerosis, Vogt-Koyanagi-Harada disease, other autoimmune syndromes, and several infectious diseases which may affect the eye. This article may serve as a guide for the diagnosis and treatment of such disorders. It should be noted that these conditions have been viewed from a neurologist's perspective thereby neurologic involvement is stressed. PMID:22454751

  16. CNS development under altered gravity

    NASA Astrophysics Data System (ADS)

    Sajdel-Sulkowska, E.

    The future of space exploration depends on a solid understanding of the developmental process under microgravity. In furtherance of this goal, the present studies assessed the impact of altered gravity on the developing rat cerebellum. Specifically, the expression of selected cerebellar proteins and corresponding genes was compared in rat neonates exposed to hypergravity (1.5G) from embryonic day (E) 11 to postnatal day (P) 6 and P9 against their expression in rat neonates developing under normal gravity. Cerebellar proteins were analyzed by quantitative western blots of cerebellar homogenates; RNA analysis was performed in the same samples using ribonuclease protection assay (RPA). Densitometric analysis of western blots suggested 21% to 31% reduction in neuronal cell adhesion molecule (NCAM) and 31% to 45% reduction in glial acidic protein (GFAP). RPA results suggested a small reduction (<10%) in NCAM mRNA and a moderate reduction (<25%) in GFAP mRNA. These data indicate that the expression of selected cerebellar proteins may be affected at both the transcriptional and translational/postranslational level. Furthermore, these results suggest that changes in expression of selected genes may underlie hypergravity's effect on the developing CNS. (Supported by NASA grant NCC2-1042 and BWH Psychiatry Fund).

  17. Transgenic petunia with the iron(III)-phytosiderophore transporter gene acquires tolerance to iron deficiency in alkaline environments.

    PubMed

    Murata, Yoshiko; Itoh, Yoshiyuki; Iwashita, Takashi; Namba, Kosuke

    2015-01-01

    Iron is an essential nutrient for all plants. However, terrestrial plants often suffer from iron deficiency in alkaline soil due to its extremely low solubility. Alkaline soil accounts for about 30% of all cultivated ground in the world. Plants have evolved two distinct strategies, I and II, for iron uptake from the soil. Dicots and non-graminaceous monocots use Strategy I, which is primarily based on the reduction of iron(III) to iron(II) and the uptake of iron(II) by the iron-regulated transporter, IRT1. In contrast, graminaceous plants use Strategy II to efficiently acquire insoluble iron(III). Strategy II comprises the synthesis and secretion of iron-chelating phytosiderophores, such as mugineic acids and the Yellow Stripe 1 transporter proteins of the iron(III)-phytosiderophore complex. Barley, which exhibits the highest tolerance to iron deficiency in alkaline soil among graminaceous plants, utilizes mugineic acids and the specific iron(III)-mugineic acids transporter, HvYS1. In this study, we established the transgenic plant Petunia hybrida, which originally had only Strategy I, by introducing the HvYS1 transporter gene derived from barley. When the transgenic plants were grown hydroponically in media containing the iron(III)-2'-deoxymugineic acid complex, free 2'-deoxymugineic acid and its iron(III) complex were detected in the root extract of the transgenic plant by electrospray ionization-Fourier transform-ion cyclotron resonance mass spectrometry. The growth of the transgenic petunia was significantly better than that of the control host in alkaline conditions. Consequently, the transgenic plant acquired a significantly enhanced tolerance to alkaline hydroponic media in the presence of the iron(III)-2'-deoxymugineic acid complex. Furthermore, the flower color of the transgenic plant deepened. The results showed that iron-phytosiderophore complexes and their transporters can potentially be utilized to overcome the worldwide iron uptake problems to diverse

  18. Expanding the role of the splicing USB1 gene from Poikiloderma with Neutropenia to acquired myeloid neoplasms.

    PubMed

    Negri, Gloria; Crescenzi, Barbara; Colombo, Elisa Adele; Fontana, Laura; Barba, Gianluca; Arcioni, Francesco; Gervasini, Cristina; Mecucci, Cristina; Larizza, Lidia

    2015-11-01

    Germline mutations of the U6 biogenesis 1 (USB1) gene underlie Poikiloderma with Neutropenia (PN), a rare autosomal recessive genodermatosis conferring an increased risk of myelodysplasia. Recent evidence highlights a key role of USB1 protein in the splicing process, but nothing is known about USB1 alterations in acquired myelodysplastic syndromes, even though mutations in the spliceosome machinery represent an ubiquitous pathway in leukaemogenesis. By molecular cytogenetics and direct sequencing, we searched for USB1 deletions/duplications and point mutations in 141 bone marrow DNA samples from patients with myelodysplastic syndromes (n = 126), myelodysplastic/myeloproliferative neoplasms (n = 12) and acute myeloid leukaemia (n = 3). Three unreported variants, two in USB1 5'UTR (c.-83G>T and c.-66A>G), one in IVS3 (c.450-68dupT) and one (<1%) in IVS4 (c.587+21A>G/rs200924980) were detected. The germline nature could be proved for the c.-66A>G, but remains undefined for c.-83G>T and c.450-68dupT. Matched controls analysis did not reveal either 5' UTR variants in 290 chromosomes and Real-time polymerase chain reaction showed a slight reduction in bone marrow RNA levels of the patient with c.-66A>G. No USB1 rearrangements were detected by interphase fluorescence in situ hybridization. This pilot investigation on USB1 expanded the variations repertoire of this gene, identifying three novel sequence variants, the role of which need further investigations in myeloid malignancies. PMID:26306619

  19. c-JUN-like immunoreactivity in the CNS of the adult rat: basal and transynaptically induced expression of an immediate-early gene.

    PubMed

    Herdegen, T; Leah, J D; Manisali, A; Bravo, R; Zimmermann, M

    1991-01-01

    An immunocytochemical study of dorsal root ganglia, spinal cord and medulla oblongata was performed with antisera against the c-jun proto-oncogene encoded protein. The c-JUN-like immunoreactivity was restricted to the cell nucleus. In the CNS of untreated rats a basal c-JUN-like immunoreactivity was present in the nuclei of two types of neurons: motor and autonomic. Labelled nuclei could be seen in many motoneurons of the ventral horn of the entire length of spinal cord and the lower medulla oblongata, as well as in the area of the nucleus hypoglossus, the dorsal motor nucleus of nucleus vagus, nucleus ambiguus, nucleus facialis, nucleus abducens and motor nucleus of nucleus trigeminus. Additionally, labelled nuclei were found in the preganglionic sympathetic and preganglionic parasympathetic cells of the nucleus intermediolateralis and nucleus intercalatus in the spinal cord. In the medulla oblongata we found a cluster of cells with c-JUN-like immunoreactivity in an area between the dorsomedial part of the oral nucleus spinalis trigeminalis and the lateral border of the knee of facial nerve. Additionally, a second cluster of c-JUN-like immunoreactivity cells was visible between the ventromedial part of the oral nucleus spinalis trigeminalis and the lateral border of the rostral nucleus facialis. Examination of the characteristics of all cell groups with a basal c-JUN-like immunoreactivity in the spinal cord and lower brainstem revealed an overlapping distribution with cholinergic cell groups. Basal c-JUN-like immunoreactivity was also seen in the dorsal root ganglion cells. We examined the factors which can effect the expression of the c-JUN protein. Maximal expression of c-JUN-like immunoreactivity was observed after electrical stimulation of primary afferents. Stimulation of sciatic nerve at a strength sufficient to recruit A delta- and C-fibres produced c-JUN-like immunoreactivity in many nuclei of the ipsilateral dorsal horn of the lumbar spinal cord. c

  20. Molecular and biochemical characterization of an endo-β-1,3-glucanase from the pinewood nematode Bursaphelenchus xylophilus acquired by horizontal gene transfer from bacteria

    PubMed Central

    2005-01-01

    We report the cloning and functional characterization of an endo-β-1,3-glucanase from the pinewood nematode Bursaphelenchus xylophilus acquired by horizontal gene transfer from bacteria. This is the first gene of this type from any nematode species. We show that a similar cDNA is also present in another closely related species B. mucronatus, but that similar sequences are not present in any other nematode studied to date. The B. xylophilus gene is expressed solely in the oesophageal gland cells of the nematode and the protein is present in the nematode's secretions. The deduced amino acid sequence of the gene is very similar to glycosyl hydrolase family 16 proteins. The recombinant protein, expressed in Escherichia coli, preferentially hydrolysed the β-1,3-glucan laminarin, and had very low levels of activity on β-1,3-1,4-glucan, lichenan and barley β-glucan. Laminarin was degraded in an endoglucanase mode by the enzyme. The optimal temperature and pH for activity of the recombinant enzyme were 65 °C and pH 4.9. The protein is probably important in allowing the nematodes to feed on fungi. Sequence comparisons suggest that the gene encoding the endo-β-1,3-glucanase was acquired by horizontal gene transfer from bacteria. B. xylophilus therefore contains genes that have been acquired by this process from both bacteria and fungi. These findings support the idea that multiple independent horizontal gene transfer events have helped in shaping the evolution of several different life strategies in nematodes. PMID:15727561

  1. Molecular and biochemical characterization of an endo-beta-1,3-glucanase from the pinewood nematode Bursaphelenchus xylophilus acquired by horizontal gene transfer from bacteria.

    PubMed

    Kikuchi, Taisei; Shibuya, Hajime; Jones, John T

    2005-07-01

    We report the cloning and functional characterization of an endo-beta-1,3-glucanase from the pinewood nematode Bursaphelenchus xylophilus acquired by horizontal gene transfer from bacteria. This is the first gene of this type from any nematode species. We show that a similar cDNA is also present in another closely related species B. mucronatus, but that similar sequences are not present in any other nematode studied to date. The B. xylophilus gene is expressed solely in the oesophageal gland cells of the nematode and the protein is present in the nematode's secretions. The deduced amino acid sequence of the gene is very similar to glycosyl hydrolase family 16 proteins. The recombinant protein, expressed in Escherichia coli, preferentially hydrolysed the beta-1,3-glucan laminarin, and had very low levels of activity on beta-1,3-1,4-glucan, lichenan and barley beta-glucan. Laminarin was degraded in an endoglucanase mode by the enzyme. The optimal temperature and pH for activity of the recombinant enzyme were 65 degrees C and pH 4.9. The protein is probably important in allowing the nematodes to feed on fungi. Sequence comparisons suggest that the gene encoding the endo-beta-1,3-glucanase was acquired by horizontal gene transfer from bacteria. B. xylophilus therefore contains genes that have been acquired by this process from both bacteria and fungi. These findings support the idea that multiple independent horizontal gene transfer events have helped in shaping the evolution of several different life strategies in nematodes. PMID:15727561

  2. Transforming Growth Factor-β1 T869C Gene Polymorphism Is Associated with Acquired Sick Sinus Syndrome via Linking a Higher Serum Protein Level

    PubMed Central

    Chen, Jan-Yow; Liu, Jiung-Hsiun; Wu, Hong-Dar Isaac; Lin, Kuo-Hung; Chang, Kuan-Cheng; Liou, Ying-Ming

    2016-01-01

    Background Familial sick sinus syndrome is associated with gene mutations and dysfunction of ion channels. In contrast, degenerative fibrosis of the sinus node tissue plays an important role in the pathogenesis of acquired sick sinus syndrome. There is a close relationship between transforming growth factor-β1 mediated cardiac fibrosis and acquired arrhythmia. It is of interest to examine whether transforming growth factor-β1 is involved in the pathogenesis of acquired sick sinus syndrome. Methods Overall, 110 patients with acquired SSS and 137 age/gender-matched controls were screened for transforming growth factor-β1 and cardiac sodium channel gene polymorphisms using gene sequencing or restriction fragment length polymorphism methods. An enzyme-linked immunosorbent assay was used to determine the serum level of transforming growth factor-β1. Results Two transforming growth factor-β1 gene polymorphisms (C-509T and T+869C) and one cardiac sodium channel gene polymorphism (H588R) have been identified. The C-dominant CC/CT genotype frequency of T869C was significantly higher in acquired sick sinus syndrome patients than in controls (OR 2.09, 95% CI 1.16–3.75, P = 0.01). Consistently, the level of serum transforming growth factor-β1 was also significantly greater in acquired sick sinus syndrome group than in controls (5.3±3.4 ng/ml vs. 3.7±2.4 ng/ml, P = 0.01). In addition, the CC/CT genotypes showed a higher transforming growth factor-β1 serum level than the TT genotype (4.25 ± 2.50 ng/ml vs. 2.71± 1.76 ng/ml, P = 0.028) in controls. Conclusion Transforming growth factor-β1 T869C polymorphism, correlated with high serum transforming growth factor-β1 levels, is associated with susceptibility to acquired sick sinus syndrome. PMID:27380173

  3. Genomic instability establishes dependencies on acquired gene regulatory networks: A novel role of p62 in myeloid malignancies with del(5q)

    PubMed Central

    Fang, Jing; Starczynowski, Daniel T

    2015-01-01

    MiR-146a deletion is a driving molecular event in del(5q) myeloid malignancies, which acquire dependency on a nuclear factor kappa B (NF-κB) regulatory network. p62, a neighboring haploid 5q gene, is induced by NF-κB and required to sustain TRAF6-mediated NF-κB activation. Interfering with p62/TRAF6 binding may have a therapeutic benefit in miR-146a–deficient leukemic cells. PMID:27308507

  4. Occurrence and analysis of irp2 virulence gene in isolates of Klebsiella pneumoniae and Enterobacter spp. from microbiota and hospital and community-acquired infections.

    PubMed

    Souza Lopes, Ana Catarina; Rodrigues, Juliana Falcão; Cabral, Adriane Borges; da Silva, Maíra Espíndola; Leal, Nilma Cintra; da Silveira, Vera Magalhães; de Morais Júnior, Marcos Antônio

    2016-07-01

    Eighty-five isolates of Klebsiella pneumoniae and Enterobacter spp., originating from hospital- and community-acquired infections and from oropharyngeal and faecal microbiota from patients in Recife-PE, Brazil, were analyzed regarding the presence of irp2 gene. This is a Yersinia typical gene involved in the synthesis of siderophore yersiniabactin. DNA sequencing confirmed the identity of irp2 gene in five K. pneumoniae, five Enterobacter aerogenes and one Enterobacter amnigenus isolates. To our knowledge in the current literature, this is the first report of the irp2 gene in E. amnigenus, a species considered an unusual human pathogen, and in K. pneumoniae and E. aerogenes isolates from the normal microbiota and from community infections, respectively. Additionally, the analyses of nucleotide and amino acid sequences suggest the irp2 genes derived from isolates used in this study are more closely related to that of Yersinia pestis P.CE882 than to that of Yersinia enterocolitica 8081. These data demonstrated that K. pneumoniae and Enterobacter spp. from normal microbiota and from community- and hospital-acquired infections possess virulence factors important for the establishment of extra-intestinal infections. PMID:27133266

  5. CNS Myelination Requires Cytoplasmic Dynein Function

    PubMed Central

    Yang, Michele L.; Shin, Jimann; Kearns, Christina A.; Langworthy, Melissa M.; Snell, Heather; Walker, Macie B.; Appel, Bruce

    2014-01-01

    Background Cytoplasmic dynein provides the main motor force for minus-end-directed transport of cargo on microtubules. Within the vertebrate central nervous system (CNS), proliferation, neuronal migration and retrograde axon transport are among the cellular functions known to require dynein. Accordingly, mutations of DYNC1H1, which encodes the heavy chain subunit of cytoplasmic dynein, have been linked to developmental brain malformations and axonal pathologies. Oligodendrocytes, the myelinating glial cell type of the CNS, migrate from their origins to their target axons and subsequently extend multiple long processes that ensheath axons with specialized insulating membrane. These processes are filled with microtubules, which facilitate molecular transport of myelin components. However, whether oligodendrocytes require cytoplasmic dynein to ensheath axons with myelin is not known. Results We identified a mutation of zebrafish dync1h1 in a forward genetic screen that caused a deficit of oligodendrocytes. Using in vivo imaging and gene expression analyses, we additionally found evidence that dync1h1 promotes axon ensheathment and myelin gene expression. Conclusions In addition to its well known roles in axon transport and neuronal migration, cytoplasmic dynein contributes to neural development by promoting myelination. PMID:25488883

  6. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.

    PubMed

    Ohashi, Kadoaki; Sequist, Lecia V; Arcila, Maria E; Moran, Teresa; Chmielecki, Juliann; Lin, Ya-Lun; Pan, Yumei; Wang, Lu; de Stanchina, Elisa; Shien, Kazuhiko; Aoe, Keisuke; Toyooka, Shinichi; Kiura, Katsuyuki; Fernandez-Cuesta, Lynnette; Fidias, Panos; Yang, James Chih-Hsin; Miller, Vincent A; Riely, Gregory J; Kris, Mark G; Engelman, Jeffrey A; Vnencak-Jones, Cindy L; Dias-Santagata, Dora; Ladanyi, Marc; Pao, William

    2012-07-31

    Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment. PMID:22773810

  7. The acquired radioresistance in HeLa cells under conditions mimicking hypoxia was attenuated by a decreased expression of HIF subunit genes induced by RNA interference

    SciTech Connect

    Doi, Nobutaka; Ogawa, Ryohei; Cui, Zheng-Guo; Morii, Akihiro; Watanabe, Akihiko; Kanayama, Shinji; Yoneda, Yuko; Kondo, Takashi

    2015-05-01

    The cancer cells residing in the hypoxic layer are resistant to radiation and these are ones responsible for cancer recurrence after radiation therapy. One of the reasons why hypoxic cancer cells acquire radioresistance may be attributable to changes in the gene expression profile by the activation of hypoxia inducible factors (HIFs). However, the details underlying this process remain unknown. In this study, we investigated the effects of knockdown of HIF subunit genes to elucidate how HIF subunit genes may be involved in the radioresistance acquired by HeLa cells following exposure to a hypoxia mimic. Interestingly, HIF-1α and HIF-2α seemed mutually complementary for each other when either of them was suppressed. We thus suppressed the expression of both genes simultaneously. To do this, we developed a short hairpin RNA (shRNA) targeting a high homology region between HIF-1α and HIF-2α. It was shown that the expression of the shRNA effectively suppressed the acquisition of radioresistance following the hypoxia mimic. Moreover, it was confirmed that suppression of both subunits resulted in the downregulation of stem cell markers and the suppression of spheroid formation during the hypoxia mimicking-conditions. This shRNA-mediated knockdown method targeting a common region shared by a family of genes may offer a new candidate cancer treatment. - Highlights: • Incubation with CoCl{sub 2} confers radioresistance to HeLa cells. • Both HIF-1α and HIF-2α are involved in the acquisition of radioresistance. • An shRNA to a homology region of HIF-1α and HIF-2α suppressed the radioresistance. • The shRNA decreased cells with stem cell markers and a stem cell phenotype.

  8. Cross-platform meta-analysis of multiple gene expression profiles identifies novel expression signatures in acquired anthracycline-resistant breast cancer.

    PubMed

    Lee, Young Seok; Ryu, Seung Won; Bae, Se Jong; Park, Tae Hwan; Kwon, Kang; Noh, Yun Hee; Kim, Sung Young

    2015-04-01

    Anthracyclines are among the most effective and commonly used chemotherapeutic agents. However, the development of acquired anthracycline resistance is a major limitation to their clinical application. The aim of the present study was to identify differentially expressed genes (DEGs) and biological processes associated with the acquisition of anthracycline resistance in human breast cancer cells. We performed a meta-analysis of publically available microarray datasets containing data on stepwise-selected, anthracycline‑resistant breast cancer cell lines using the RankProd package in R. Additionally, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to analyze GO term enrichment and pathways, respectively. A protein-protein interaction (PPI) network was also generated using Cytoscape software. The meta-analysis yielded 413 DEGs related to anthracycline resistance in human breast cancer cells, and 374 of these were not involved in individual DEGs. GO analyses showed the 413 genes were enriched with terms such as 'response to steroid metabolic process', 'chemical stimulus', 'external stimulus', 'hormone stimulus', 'multicellular organismal process', and 'system development'. Pathway analysis revealed significant pathways including steroid hormone biosynthesis, cytokine-cytokine receptor interaction, drug metabolism-cytochrome P450, metabolism of xenobiotics by cytochrome P450, and arachidonic acid metabolism. The PPI network indicated that proteins encoded by TRIM29, VTN, CCNA1, and karyopherin α 5 (KPNA5) participated in a significant number of interactions. In conclusion, our meta-analysis provides a comprehensive view of gene expression patterns associated with acquired resistance to anthracycline in breast cancer cells, and constitutes the basis for additional functional studies. PMID:25695524

  9. Acquired hyperpigmentations*

    PubMed Central

    Cestari, Tania Ferreira; Dantas, Lia Pinheiro; Boza, Juliana Catucci

    2014-01-01

    Cutaneous hyperpigmentations are frequent complaints, motivating around 8.5% of all dermatological consultations in our country. They can be congenital, with different patterns of inheritance, or acquired in consequence of skin problems, systemic diseases or secondary to environmental factors. The vast majority of them are linked to alterations on the pigment melanin, induced by different mechanisms. This review will focus on the major acquired hyperpigmentations associated with increased melanin, reviewing their mechanisms of action and possible preventive measures. Particularly prominent aspects of diagnosis and therapy will be emphasized, with focus on melasma, post-inflammatory hyperpigmentation, periorbital pigmentation, dermatosis papulosa nigra, phytophotodermatoses, flagellate dermatosis, erythema dyschromicum perstans, cervical poikiloderma (Poikiloderma of Civatte), acanthosis nigricans, cutaneous amyloidosis and reticulated confluent dermatitis PMID:24626644

  10. High Polyhydroxybutyrate Production in Pseudomonas extremaustralis Is Associated with Differential Expression of Horizontally Acquired and Core Genome Polyhydroxyalkanoate Synthase Genes

    PubMed Central

    Catone, Mariela V.; Ruiz, Jimena A.; Castellanos, Mildred; Segura, Daniel; Espin, Guadalupe; López, Nancy I.

    2014-01-01

    Pseudomonas extremaustralis produces mainly polyhydroxybutyrate (PHB), a short chain length polyhydroxyalkanoate (sclPHA) infrequently found in Pseudomonas species. Previous studies with this strain demonstrated that PHB genes are located in a genomic island. In this work, the analysis of the genome of P. extremaustralis revealed the presence of another PHB cluster phbFPX, with high similarity to genes belonging to Burkholderiales, and also a cluster, phaC1ZC2D, coding for medium chain length PHA production (mclPHA). All mclPHA genes showed high similarity to genes from Pseudomonas species and interestingly, this cluster also showed a natural insertion of seven ORFs not related to mclPHA metabolism. Besides PHB, P. extremaustralis is able to produce mclPHA although in minor amounts. Complementation analysis demonstrated that both mclPHA synthases, PhaC1 and PhaC2, were functional. RT-qPCR analysis showed different levels of expression for the PHB synthase, phbC, and the mclPHA synthases. The expression level of phbC, was significantly higher than the obtained for phaC1 and phaC2, in late exponential phase cultures. The analysis of the proteins bound to the PHA granules showed the presence of PhbC and PhaC1, whilst PhaC2 could not be detected. In addition, two phasin like proteins (PhbP and PhaI) associated with the production of scl and mcl PHAs, respectively, were detected. The results of this work show the high efficiency of a foreign gene (phbC) in comparison with the mclPHA core genome genes (phaC1 and phaC2) indicating that the ability of P. extremaustralis to produce high amounts of PHB could be explained by the different expression levels of the genes encoding the scl and mcl PHA synthases. PMID:24887088

  11. High polyhydroxybutyrate production in Pseudomonas extremaustralis is associated with differential expression of horizontally acquired and core genome polyhydroxyalkanoate synthase genes.

    PubMed

    Catone, Mariela V; Ruiz, Jimena A; Castellanos, Mildred; Segura, Daniel; Espin, Guadalupe; López, Nancy I

    2014-01-01

    Pseudomonas extremaustralis produces mainly polyhydroxybutyrate (PHB), a short chain length polyhydroxyalkanoate (sclPHA) infrequently found in Pseudomonas species. Previous studies with this strain demonstrated that PHB genes are located in a genomic island. In this work, the analysis of the genome of P. extremaustralis revealed the presence of another PHB cluster phbFPX, with high similarity to genes belonging to Burkholderiales, and also a cluster, phaC1ZC2D, coding for medium chain length PHA production (mclPHA). All mclPHA genes showed high similarity to genes from Pseudomonas species and interestingly, this cluster also showed a natural insertion of seven ORFs not related to mclPHA metabolism. Besides PHB, P. extremaustralis is able to produce mclPHA although in minor amounts. Complementation analysis demonstrated that both mclPHA synthases, PhaC1 and PhaC2, were functional. RT-qPCR analysis showed different levels of expression for the PHB synthase, phbC, and the mclPHA synthases. The expression level of phbC, was significantly higher than the obtained for phaC1 and phaC2, in late exponential phase cultures. The analysis of the proteins bound to the PHA granules showed the presence of PhbC and PhaC1, whilst PhaC2 could not be detected. In addition, two phasin like proteins (PhbP and PhaI) associated with the production of scl and mcl PHAs, respectively, were detected. The results of this work show the high efficiency of a foreign gene (phbC) in comparison with the mclPHA core genome genes (phaC1 and phaC2) indicating that the ability of P. extremaustralis to produce high amounts of PHB could be explained by the different expression levels of the genes encoding the scl and mcl PHA synthases. PMID:24887088

  12. Neurofibromatosis Type 1: Modeling CNS Dysfunction

    PubMed Central

    Gutmann, David H.; Parada, Luis F.; Silva, Alcino J.; Ratner, Nancy

    2012-01-01

    Neurofibromatosis type 1 (NF1) is the most common monogenic disorder in which individuals manifest central nervous system (CNS) abnormalities. Affected individuals develop glial neoplasms (optic gliomas, malignant astrocytomas) and neuronal dysfunction (learning disabilities, attention deficits). Nf1 genetically-engineered mouse models have revealed the molecular and cellular underpinnings of gliomagenesis, attention deficit, and learning problems with relevance to basic neurobiology. Using NF1 as a model system, these studies have revealed critical roles for the NF1 gene in non-neoplastic cells in the tumor microenvironment, the importance of brain region heterogeneity, novel mechanisms of glial growth regulation, the neurochemical bases for attention deficit and learning abnormalities, and new insights into neural stem cell function. Here we review recent studies, presented at a symposium at the 2012 Society for Neuroscience annual meeting, that highlight unexpected cell biology insights into RAS and cyclic AMP pathway effects on neural progenitor signaling, neuronal function, and oligodendrocyte lineage differentiation. PMID:23055477

  13. Cytokine-mediated inflammation, tumorigenesis, and disease-associated JAK/STAT/SOCS signaling circuits in the CNS.

    PubMed

    Campbell, Iain L

    2005-04-01

    Cytokines are plurifunctional mediators of cellular communication. The CNS biology of this family of molecules has been explored by transgenic approaches that targeted the expression of individual cytokine genes to specific cells in the CNS of mice. Such transgenic animals exhibit wide-ranging structural and functional alterations that are linked to the development of distinct neuroinflammatory responses and gene expression profiles specific for each cytokine. The unique actions of individual cytokines result from the activation of specific receptor-coupled cellular signal transduction pathways such as the JAK/STAT tyrosine kinase signaling cascade. The cerebral expression of various STATs, their activation, as well as that of the major physiological inhibitors of this pathway, SOCS1 and SOCS3, is highly regulated in a stimulus- and cell-specific fashion. The role of the key IFN signaling molecules STAT1 or STAT2 was studied in transgenic mice (termed GIFN) with astrocyte-production of IFN-alpha that were null or haploinsufficient for these STAT genes. Surprisingly, these animals developed either more severe and accelerated neurodegeneration with calcification and inflammation (GIFN/STAT1 deficient) or severe immunoinflammation and medulloblastoma (GIFN/STAT2 deficient). STAT dysregulation may result in a signal switch phenomenon in which one cytokine acquires the apparent function of an entirely different cytokine. Therefore, for cytokines such as the IFNs, the receptor-coupled signaling process is complex, involving the coexistence of multiple JAK/STAT as well as alternative pathways. The cellular compartmentalization and balance in the activity of these pathways ultimately determines the repertoire and nature of CNS cytokine actions. PMID:15850655

  14. Cloning and expression analysis of cDNAs corresponding to genes activated in cucumber showing systemic acquired resistance after BTH treatment

    PubMed Central

    Bovie, Catherine; Ongena, Marc; Thonart, Philippe; Dommes, Jacques

    2004-01-01

    Background Infection of plants by necrotizing pathogens can lead to the rapid and localized induction of a complex set of defense responses resulting in a restriction of pathogen growth and spread. Subsequently, an increase of plant resistance against a broad spectrum of pathogens is observed systemically. This plant immunity is known as Systemic Acquired Resistance. To identify components of the transduction pathway, we cloned and analysed the expression pattern of several mRNAs accumulating in cucumber plants after induction of Systemic Acquired Resistance. Results We tested on cucumber different compounds known to induce systemic acquired resistance. Among these, BTH (benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester) proved to be very effective. mRNA RT-PCR differential display was used to identify mRNA sequences induced 24 hours after the application of 10 μM BTH to cucumber plants. A cDNA library constructed from cucumber plants sprayed with 10 μM BTH was screened to get corresponding full length cDNAs. Among the identified cDNAs were those coding for a putative ras-related GTP-binding protein, a putative beta-1,4-N-Acetylglucosaminyltranferase III and a putative pathogenesis related protein. The time course of accumulation of the three corresponding mRNAs was analysed by northern blotting in plants treated by BTH or in plants infected by Colletotrichum lagenarium. Conclusions The mRNA RT-PCR differential display technique allowed the identification of three genes possibly involved in Systemic Acquired Resistance in cucumber. Pathogenesis-related proteins are known to be involved in plant defence against pathogens. GTP-binding protein and N-acetylglucosaminyltranferase III have been reported to be components of signal transduction pathways in mammals and plants. PMID:15331019

  15. Role of OXA-23 and AdeABC efflux pump for acquiring carbapenem resistance in an Acinetobacter baumannii strain carrying the blaOXA-66 gene.

    PubMed

    Lee, Yangsoon; Yum, Jong Hwa; Kim, Chang-Ki; Yong, Dongeun; Jeon, Eun Hee; Jeong, Seok Hoon; Ahn, Jee Young; Lee, Kyungwon

    2010-01-01

    This study was performed to determine the mechanisms for acquiring carbapenem resistance in six clinical isolates of Acinetobacter baumannii. All isolates showed similar SmaI-macrorestriction patterns with less than 3 band differences by PFGE. The isolates showed a high level resistance (>32 mg/L) to both imipenem and meropenem by Etest. Phe-Arg-beta-naphthylamide lowered the MICs of carbapenems. Real-time PCR experiments showed that expression levels of the adeB gene in the six A. baumannii isolates were 10- to 40-times higher than those of imipenem-susceptible strains. Direct sequencing of PCR products showed that all isolates carried the bla(OXA-23) gene, which was preceded by ISAba1. The bla(OXA-23) probe hybridized with approximately 500-kb I-CeuI chromosomal fragments, but not with a plasmid. These findings suggest that overexpression of the AdeABC efflux pump as well as chromosome-borne OXA-23 may play a role in acquiring carbapenem resistance in our A. baumannii isolates. PMID:20124329

  16. Antibacterial resistance, genes encoding toxins and genetic background among Staphylococcus aureus isolated from community-acquired skin and soft tissue infections in France: a national prospective survey.

    PubMed

    Lamy, B; Laurent, F; Gallon, O; Doucet-Populaire, F; Etienne, J; Decousser, J-W

    2012-06-01

    The epidemiology of staphylococcal community-acquired skin and soft tissues infections (CA-SSTIs) has changed dramatically. We described prospectively the characteristics of the Staphylococcus aureus isolated from 71 non-teaching French hospitals and implicated in CA-SSTIs: antimicrobial susceptibility (mecA polymerase chain reaction [PCR], disk diffusion method), virulence factor gene (sea, tst, pvl) prevalence and genetic background (agr allele). During November 2006, 235 strains were collected (wound infection: 51%, abscess: 21%, whitlow: 8%, diabetic foot: 7%, furunculosis: 3%). sea, tst and pvl were identified in 22.1, 13.2 and 8.9% strains, respectively. agr allele 1 was the most frequently encountered genetic background, whatever the methicillin susceptibility. Among the 34 methicillin-resistant S. aureus (MRSA, 14.5% of all S. aureus), only one strain (2.9%) harboured pvl (belonging to the European ST80 clone), four (11.8%) tst (belonging to two endemic French clones) and 18 (52.9%) sea gene (mainly the Lyon clone). According to their in vitro activity, pristinamycin or trimethoprim/sulfamethoxazole could be considered as first-choice antibiotics. To date, the international pvl-positive MRSA clones have not spread in France. MRSA strains isolated from putative CA-SSTIs exhibited a genetic and phenotypic background of hospital-acquired (HA) clones. National survey should be continued, in order to monitor the emergence of virulent clones. PMID:21997773

  17. Mammalian-specific genomic functions: Newly acquired traits generated by genomic imprinting and LTR retrotransposon-derived genes in mammals

    PubMed Central

    KANEKO-ISHINO, Tomoko; ISHINO, Fumitoshi

    2015-01-01

    Mammals, including human beings, have evolved a unique viviparous reproductive system and a highly developed central nervous system. How did these unique characteristics emerge in mammalian evolution, and what kinds of changes did occur in the mammalian genomes as evolution proceeded? A key conceptual term in approaching these issues is “mammalian-specific genomic functions”, a concept covering both mammalian-specific epigenetics and genetics. Genomic imprinting and LTR retrotransposon-derived genes are reviewed as the representative, mammalian-specific genomic functions that are essential not only for the current mammalian developmental system, but also mammalian evolution itself. First, the essential roles of genomic imprinting in mammalian development, especially related to viviparous reproduction via placental function, as well as the emergence of genomic imprinting in mammalian evolution, are discussed. Second, we introduce the novel concept of “mammalian-specific traits generated by mammalian-specific genes from LTR retrotransposons”, based on the finding that LTR retrotransposons served as a critical driving force in the mammalian evolution via generating mammalian-specific genes. PMID:26666304

  18. Cognitive Function Related to the Sirh11/Zcchc16 Gene Acquired from an LTR Retrotransposon in Eutherians

    PubMed Central

    Irie, Masahito; Yoshikawa, Masanobu; Ono, Ryuichi; Iwafune, Hirotaka; Furuse, Tamio; Yamada, Ikuko; Wakana, Shigeharu; Yamashita, Yui; Abe, Takaya; Ishino, Fumitoshi; Kaneko-Ishino, Tomoko

    2015-01-01

    Gene targeting of mouse S ushi- i chi-related r etrotransposon h omologue 11 / Z inc finger CCHC domain-containing 16 (Sirh11/Zcchc16) causes abnormal behaviors related to cognition, including attention, impulsivity and working memory. Sirh11/Zcchc16 encodes a CCHC type of zinc-finger protein that exhibits high homology to an LTR retrotransposon Gag protein. Upon microdialysis analysis of the prefrontal cortex region, the recovery rate of noradrenaline (NA) was reduced compared with dopamine (DA) after perfusion of high potassium-containing artificial cerebrospinal fluid in knockout (KO) mice. These data indicate that Sirh11/Zcchc16 is involved in cognitive function in the brain, possibly via the noradrenergic system, in the contemporary mouse developmental systems. Interestingly, it is highly conserved in three out of the four major groups of the eutherians, euarchontoglires, laurasiatheria and afrotheria, but is heavily mutated in xenarthran species such as the sloth and armadillo, suggesting that it has contributed to brain evolution in the three major eutherian lineages, including humans and mice. Sirh11/Zcchc16 is the first SIRH gene to be involved in brain function, instead of just the placenta, as seen in the case of Peg10, Peg11/Rtl1 and Sirh7/Ldoc1. PMID:26402067

  19. Cognitive Function Related to the Sirh11/Zcchc16 Gene Acquired from an LTR Retrotransposon in Eutherians.

    PubMed

    Irie, Masahito; Yoshikawa, Masanobu; Ono, Ryuichi; Iwafune, Hirotaka; Furuse, Tamio; Yamada, Ikuko; Wakana, Shigeharu; Yamashita, Yui; Abe, Takaya; Ishino, Fumitoshi; Kaneko-Ishino, Tomoko

    2015-09-01

    Gene targeting of mouse Sushi-ichi-related retrotransposon homologue 11/Zinc finger CCHC domain-containing 16 (Sirh11/Zcchc16) causes abnormal behaviors related to cognition, including attention, impulsivity and working memory. Sirh11/Zcchc16 encodes a CCHC type of zinc-finger protein that exhibits high homology to an LTR retrotransposon Gag protein. Upon microdialysis analysis of the prefrontal cortex region, the recovery rate of noradrenaline (NA) was reduced compared with dopamine (DA) after perfusion of high potassium-containing artificial cerebrospinal fluid in knockout (KO) mice. These data indicate that Sirh11/Zcchc16 is involved in cognitive function in the brain, possibly via the noradrenergic system, in the contemporary mouse developmental systems. Interestingly, it is highly conserved in three out of the four major groups of the eutherians, euarchontoglires, laurasiatheria and afrotheria, but is heavily mutated in xenarthran species such as the sloth and armadillo, suggesting that it has contributed to brain evolution in the three major eutherian lineages, including humans and mice. Sirh11/Zcchc16 is the first SIRH gene to be involved in brain function, instead of just the placenta, as seen in the case of Peg10, Peg11/Rtl1 and Sirh7/Ldoc1. PMID:26402067

  20. Ontogeny and functions of CNS macrophages

    PubMed Central

    Katsumoto, Atsuko; Lu, Haiyan; Miranda, Aline S.; Ransohoff, Richard M.

    2014-01-01

    Microglia, the only non-neuroepithelial cells found in the parenchyma of the central nervous system (CNS), originate during embryogenesis from the yolk sac and enter the CNS quite early (embryonic day 9.5-10 in mice). Thereafter, microglia are maintained independently of any input from the blood and in particular do not require hematopoietic stem cells as a source of replacement for senescent cells. Monocytes are hematopoietic cells, derived from bone marrow. The ontogeny of microglia and monocytes is important for understanding CNS pathologies. Microglial functions are distinct from those of blood-derived monocytes, which invade the CNS only under pathological conditions. Recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis and synaptic interactions. Here we discuss physiology of microglia and the functions of monocytes in CNS pathology. We address the roles of microglia and monocytes in neurodegenerative diseases as an example of CNS pathology. PMID:25193935

  1. Animal models of CNS disorders.

    PubMed

    McGonigle, Paul

    2014-01-01

    There is intense interest in the development and application of animal models of CNS disorders to explore pathology and molecular mechanisms, identify potential biomarkers, and to assess the therapeutic utility, estimate safety margins and establish pharmacodynamic and pharmacokinetic parameters of new chemical entities (NCEs). This is a daunting undertaking, due to the complex and heterogeneous nature of these disorders, the subjective and sometimes contradictory nature of the clinical endpoints and the paucity of information regarding underlying molecular mechanisms. Historically, these models have been invaluable in the discovery of therapeutics for a range of disorders including anxiety, depression, schizophrenia, and Parkinson's disease. Recently, however, they have been increasingly criticized in the wake of numerous clinical trial failures of NCEs with promising preclinical profiles. These failures have resulted from a number of factors including inherent limitations of the models, over-interpretation of preclinical results and the complex nature of clinical trials for CNS disorders. This review discusses the rationale, strengths, weaknesses and predictive validity of the most commonly used models for psychiatric, neurodegenerative and neurological disorders as well as critical factors that affect the variability and reproducibility of these models. It also addresses how progress in molecular genetics and the development of transgenic animals has fundamentally changed the approach to neurodegenerative disorder research. To date, transgenic animal models\\have not been the panacea for drug discovery that many had hoped for. However continual refinement of these models is leading to steady progress with the promise of eventual therapeutic breakthroughs. PMID:23811310

  2. Protein arginine methyltransferase 1 may be involved in pregnane x receptor-activated overexpression of multidrug resistance 1 gene during acquired multidrug resistant

    PubMed Central

    Li, Tingting; Kong, Ah-Ng Tony; Ma, Zhiqiang; Liu, Haiyan; Liu, Pinghua; Xiao, Yu; Jiang, Xuehua; Wang, Ling

    2016-01-01

    Purpose Pregnane x receptor (PXR) - activated overexpression of the multidrug resistance 1 (MDR1) gene is an important way for tumor cells to acquire drug resistance. However, the detailed mechanism still remains unclear. In the present study, we aimed to investigate whether protein arginine methyl transferase 1(PRMT1) is involved in PXR - activated overexpression of MDR1 during acquired multidrug resistant. Experimental Design Arginine methyltransferase inhibitor 1 (AMI-1) was used to pharmacologically block PRMT1 in resistant breast cancer cells (MCF7/adr). The mRNA and protein levels of MDR1 were detected by real-time PCR and western blotting analysis. Immunofluorescence microscopy and co-immunoprecipitation were used to investigate the physical interaction between PXR and PRMT1. Then, 136 candidate compounds were screened for PRMT1 inhibitors. Lastly, luciferase reporter gene and nude mice bearing resistant breast cancer xenografts were adopted to investigate the anti-tumor effect of PRMT1 inhibitors when combined with adriamycin. Results AMI-1 significantly suppressed the expression of MDR1 in MCF7/adr cells and increased cells sensitivity of MCF7/adr to adriamycin. Physical interaction between PRMT1 and PXR exists in MCF7/adr cells, which could be disrupted by AMI-1. Those results suggest that PRMT1 may be involved in PXR-activated overexpression of MDR1 in resistant breast cancer cells, and AMI-1 may suppress MDR1 by disrupting the interaction between PRMT1 and PXR. Then, five compounds including rutin, isoquercitrin, salvianolic acid A, naproxen, and felodipline were identified to be PRMT1 inhibitors. Finally, those PRMT1 inhibitors were observed to significantly decrease MDR1 promoter activity in vitro and enhance the antitumor effect of adriamycin in nude mice that bearing resistant breast cancer xenografts. Conclusions PRMT1 may be an important co-activator of PXR in activating MDR1 gene during acquired resistance, and PRMT1 inhibitor combined with

  3. Dissection of larval CNS in Drosophila melanogaster.

    PubMed

    Hafer, Nathaniel; Schedl, Paul

    2006-12-01

    The central nervous system (CNS) of Drosophila larvae is complex and poorly understood. One way to investigate the CNS is to use immunohistochemistry to examine the expression of various novel and marker proteins. Staining of whole larvae is impractical because the tough cuticle prevents antibodies from penetrating inside the body cavity. In order to stain these tissues it is necessary to dissect the animal prior to fixing and staining. In this article we demonstrate how to dissect Drosophila larvae without damaging the CNS. Begin by tearing the larva in half with a pair of fine forceps, and then turn the cuticle "inside-out" to expose the CNS. If the dissection is performed carefully the CNS will remain attached to the cuticle. We usually keep the CNS attached to the cuticle throughout the fixation and staining steps, and only completely remove the CNS from the cuticle just prior to mounting the samples on glass slides. We also show some representative images of a larval CNS stained with Eve, a transcription factor expressed in a subset of neurons in the CNS. The article concludes with a discussion of some of the practical uses of this technique and the potential difficulties that may arise. PMID:18704179

  4. CNS: sex steroids and SERMs.

    PubMed

    Bernardi, F; Pluchino, N; Stomati, M; Pieri, M; Genazzani, A R

    2003-11-01

    The central nervous system (CNS) is one of the main target tissues for sex steroid hormones, which act both through genomic mechanisms, modulating synthesis, release, and metabolism of many neuropeptides and neurotransmitters, and through nongenomic mechanisms, influencing electrical excitability, synaptic function, and morphological features. The identification of the brain as a de novo source of neurosteroids modulating cerebral function, suggests that the modifications in mood and cognitive performances occurring in postmenopausal women could also be related to a modification in the levels of neurosteroids, particularly allopregnanolone and DHEA, GABA-A agonist, and antagonist, respectively. The selective estrogen receptor modulators (SERMs) are compounds that activate the estrogen receptors with different estrogenic and antiestrogenic tissue-specific effects. In addition to the effects of the classic steroid hormones on the CNS, the study of selective estrogen receptor modulators impact on the neuroendocrine system has recently provided encouraging results, indicating that raloxifene analog LY 117018 and the new generation SERM EM-652 have an estrogen-like action on beta-endorphin and on allopregnanolone in ovariectomized rats, while they exert an anti-estrogenic effect in fertile rats and in ovariectomized rats treated with estrogens. In addition, raloxifene administration in postmenopausal women plays an estrogen-like effect on circulating beta-EP and allopregnanolone levels, and it restores the response of beta-EP and allopregnanolone to neuroendocrine tests. In conclusion, the positive effects of HRT on mood and cognition in postmenopausal women occur via the modulation of neuroendocrine pathways and probably also of neurosteroidogenesis. The effects of raloxifene on mood and cognition encourage the efforts in the research of an ideal estrogen replacement therapy, showing all the positive effects of estrogens and fewer side effects. PMID:14644845

  5. Applications of Genomic Sequencing in Pediatric CNS Tumors.

    PubMed

    Bavle, Abhishek A; Lin, Frank Y; Parsons, D Williams

    2016-05-01

    Recent advances in genome-scale sequencing methods have resulted in a significant increase in our understanding of the biology of human cancers. When applied to pediatric central nervous system (CNS) tumors, these remarkable technological breakthroughs have facilitated the molecular characterization of multiple tumor types, provided new insights into the genetic basis of these cancers, and prompted innovative strategies that are changing the management paradigm in pediatric neuro-oncology. Genomic tests have begun to affect medical decision making in a number of ways, from delineating histopathologically similar tumor types into distinct molecular subgroups that correlate with clinical characteristics, to guiding the addition of novel therapeutic agents for patients with high-risk or poor-prognosis tumors, or alternatively, reducing treatment intensity for those with a favorable prognosis. Genomic sequencing has also had a significant impact on translational research strategies in pediatric CNS tumors, resulting in wide-ranging applications that have the potential to direct the rational preclinical screening of novel therapeutic agents, shed light on tumor heterogeneity and evolution, and highlight differences (or similarities) between pediatric and adult CNS tumors. Finally, in addition to allowing the identification of somatic (tumor-specific) mutations, the analysis of patient-matched constitutional (germline) DNA has facilitated the detection of pathogenic germline alterations in cancer genes in patients with CNS tumors, with critical implications for genetic counseling and tumor surveillance strategies for children with familial predisposition syndromes. As our understanding of the molecular landscape of pediatric CNS tumors continues to advance, innovative applications of genomic sequencing hold significant promise for further improving the care of children with these cancers. PMID:27188671

  6. Synechococcus sp. PCC7942 Transformed with Escherichia coli bet Genes Produces Glycine Betaine from Choline and Acquires Resistance to Salt Stress.

    PubMed Central

    Nomura, M.; Ishitani, M.; Takabe, T.; Rai, A. K.; Takabe, T.

    1995-01-01

    Synechococcus sp. PCC7942, a fresh water cyanobacterium, was transformed by a shuttle plasmid that contains a 9-kb fragment encoding the Escherichia coli bet gene cluster, i.e. betA (choline dehydrogenase), betB (betaine aldehyde dehydrogenase), betI (a putative regulatory protein), and betT (the choline transport system). The expression of these genes was demonstrated in the cyanobacterial cells (bet-containing cells) by northern blot analysis, as well as by the detection of glycine betaine by 1H nuclear magnetic resonance in cells supplemented with choline. Endogenous choline was not detected in either control or bet-containing cells. Both control and bet-containing cyanobacterial cells were found to import choline in an energy-dependent process, although this import was restricted only to bet-containing cells in conditions of salt stress. Glycine betaine was found to accumulate to a concentration of 45 mM in bet-containing cyanobacterial cells, and this resulted in a stabilization of the photosynthetic activities of photosystems I and II, higher phycobilisome contents, and general protective effects against salt stress when compared to control cells. The growth of bet-containing cells was much faster in the presence of 0.375 M NaCl than that of control cells, indicating that the transformant acquired resistance to salt stress. PMID:12228394

  7. Incidence of community-acquired methicillin-resistant Staphylococcus aureus carrying Pantone-Valentine leucocidin gene at a referral hospital in United Arab Emirates.

    PubMed

    Dash, Nihar; Panigrahi, Debadatta; Al Zarouni, Mansour; Yassin, Faten; Al-Shamsi, Moza

    2014-04-01

    Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging pathogen in hospitalized patients worldwide. The present study was undertaken to identify CA-MRSA in hospitalized patients in a 350-bed tertiary care hospital in Sharjah, UAE over a 2-year period from January 2011 to December 2012. CA-MRSA was defined based on identification within first 48 h of admission in the hospital. Staphylococcal cassette chromosome (SCC) mec typing of the CA-MRSA isolates was carried out by multiplex polymerase chain reaction (PCR). Detection of PVL and mecA genes was done by PCR using the GenoType(®) MRSA test system (Hain Lifescience). Patient's clinical data and antimicrobial susceptibility pattern of the CA-MRSA isolates were also evaluated. Fifty seven of the 187 MRSA isolates were identified as CA-MRSA. All the CA-MRSA strains in our study belonged to SCCmecIV type and were positive for both PVL and mecA genes. The patients with CA-MRSA infections were young (median age, 32 years) and the majority of infections involved the skin and soft tissue (36%). Antimicrobial susceptibility pattern of the CA-MRSA isolates showed a better susceptibility profile to the non-beta-lactam antimicrobials with the exception of ciprofloxacin having 28% resistance. This study evidently strengthens the recent observation of an increase in CA-MRSA emergence among hospitalized patients in the UAE. PMID:23919760

  8. Revisiting the Mechanisms of CNS Immune Privilege.

    PubMed

    Louveau, Antoine; Harris, Tajie H; Kipnis, Jonathan

    2015-10-01

    Whereas the study of the interactions between the immune system and the central nervous system (CNS) has often focused on pathological conditions, the importance of neuroimmune communication in CNS homeostasis and function has become clear over that last two decades. Here we discuss the progression of our understanding of the interaction between the peripheral immune system and the CNS. We examine the notion of immune privilege of the CNS in light of both earlier findings and recent studies revealing a functional meningeal lymphatic system that drains cerebrospinal fluid (CSF) to the deep cervical lymph nodes, and consider the implications of a revised perspective on the immune privilege of the CNS on the etiology and pathology of different neurological disorders. PMID:26431936

  9. CNS disease triggering Takotsubo stress cardiomyopathy.

    PubMed

    Finsterer, Josef; Wahbi, Karim

    2014-12-15

    There are a number of hereditary and non-hereditary central nervous system (CNS) disorders, which directly or indirectly affect the heart (brain-heart disorders). The most well-known of these CNS disorders are epilepsy, stroke, infectious or immunological encephalitis/meningitis, migraine, and traumatic brain injury. In addition, a number of hereditary and non-hereditary neurodegenerative disorders may impair cardiac functions. Affection of the heart may manifest not only as arrhythmias, myocardial infarction, autonomic impairment, systolic dysfunction/heart failure, arterial hypertension, or pulmonary hypertension, but also as stress cardiomyopathy (Takotsubo syndrome, TTS). CNS disease triggering TTS includes subarachnoid bleeding, epilepsy, ischemic stroke, intracerebral bleeding, migraine, encephalitis, traumatic brain injury, PRES syndrome, or ALS. Usually, TTS is acutely precipitated by stress triggered by various different events. TTS is one of the cardiac abnormalities most frequently induced by CNS disorders. Appropriate management of TTS from CNS disorders is essential to improve the outcome of affected patients. PMID:25213573

  10. Inhibition of hyaluronan synthesis protects against central nervous system (CNS) autoimmunity and increases CXCL12 expression in the inflamed CNS.

    PubMed

    Mueller, Andre Michael; Yoon, Bo Hyung; Sadiq, Saud Ahmed

    2014-08-15

    Hyaluronan (HA) may have proinflammatory roles in the context of CNS autoimmunity. It accumulates in demyelinated multiple sclerosis (MS) lesions, promotes antigen presentation, and enhances T-cell activation and proliferation. HA facilitates lymphocyte binding to vessels and CNS infiltration at the CNS vascular endothelium. Furthermore, HA signals through Toll-like receptors 2 and 4 to stimulate inflammatory gene expression. We assessed the role of HA in experimental autoimmune encephalomyelitis (EAE), an animal model of MS by administration of 4-methylumbelliferone (4MU), a well established inhibitor of HA synthesis. 4MU decreased hyaluronan synthesis in vitro and in vivo. It was protective in active EAE of C57Bl/6 mice, decreased spinal inflammatory infiltrates and spinal infiltration of Th1 cells, and increased differentiation of regulatory T-cells. In adoptive transfer EAE, feeding of 4MU to donor mice significantly decreased the encephalitogenicity of lymph node cells. The transfer of proteolipid protein (PLP)-stimulated lymph node cells to 4MU-fed mice resulted in a delayed EAE onset and delayed spinal T-cell infiltration. Expression of CXCL12, an anti-inflammatory chemokine, is reduced in MS patients in CSF cells and in spinal cord tissue during EAE. Hyaluronan suppressed production of CXCL12, whereas 4MU increased spinal CXCL12 in naive animals and during neuroinflammation. Neutralization of CXCR4, the most prominent receptor of CXCL12, by administration of AMD3100 diminished the protective impact of 4MU in adoptive transfer EAE. In conclusion, hyaluronan exacerbates CNS autoimmunity, enhances encephalitogenic T-cell responses, and suppresses the protective chemokine CXCL12 in CNS tissue. Inhibition of hyaluronan synthesis with 4MU protects against an animal model of MS and may represent an important therapeutic option in MS and other neuroinflammatory diseases. PMID:24973214

  11. Detection of New Methicillin-Resistant Staphylococcus aureus Clones Containing the Toxic Shock Syndrome Toxin 1 Gene Responsible for Hospital- and Community-Acquired Infections in France

    PubMed Central

    Durand, Geraldine; Bes, Michèle; Meugnier, Helene; Enright, Mark C.; Forey, Françoise; Liassine, Nadia; Wenger, Aline; Kikuchi, Ken; Lina, Gerard; Vandenesch, François; Etienne, Jerome

    2006-01-01

    Methicillin-resistant Staphylococcus aureus (MRSA) clones harboring the toxic shock syndrome toxin 1 (tst) gene have been detected in France and in Switzerland since 2002. During a passive survey conducted between 2002 and 2003, we collected 103 tst-positive S. aureus isolates from 42 towns in France, of which 27 were resistant to methicillin. The tst-positive MRSA belonged to two clones: a major clone comprising 25 isolates of sequence type (ST) 5 and agr group 2 and a minor clone comprising two isolates of ST30 and agr3. The tst-positive MRSA clones were associated with both hospital-acquired (12 cases) and community-acquired (8 cases) infections. The MRSA clones were mainly isolated from children (overall median age, 3 years). They caused a variety of clinical syndromes, including toxic shock syndrome and suppurative infections. Both clones were found to harbor a type IV staphylococcal chromosomal cassette mec (SCCmec) and to have similar antibiotic resistance profiles (usually resistant to oxacillin, kanamycin, and tobramycin and with intermediate resistance to fusidic acid). The origin of these clones is unclear. The tst-positive agr2 MRSA clone has the same sequence type (ST5) of two pandemic nosocomial MRSA clones, namely, the Pediatric clone and the New York/Japan clone. These findings suggest that all these clones are phylogenetically related. The pulsotype of the tst-positive MRSA clones differed from that of methicillin-sensitive S. aureus (MSSA) clones by a single band involving the SCCmec element. These findings suggest that the tst-positive MRSA clones may have emerged from their respective MSSA counterparts. PMID:16517865

  12. Clitoria ternatea and the CNS.

    PubMed

    Jain, Neeti N; Ohal, C C; Shroff, S K; Bhutada, R H; Somani, R S; Kasture, V S; Kasture, S B

    2003-06-01

    The present investigation was aimed at determining the spectrum of activity of the methanolic extract of Clitoria ternatea (CT) on the CNS. The CT was studied for its effect on cognitive behavior, anxiety, depression, stress and convulsions induced by pentylenetetrazol (PTZ) and maximum electroshock (MES). To explain these effects, the effect of CT was also studied on behavior mediated by dopamine (DA), noradrenaline, serotonin and acetylcholine. The extract decreased time required to occupy the central platform (transfer latency, TL) in the elevated plus maze (EPM) and increased discrimination index in the object recognition test, indicating nootropic activity. The extract was more active in the object recognition test than in the EPM. The extract increased occupancy in the open arm of EPM by 160% and in the lit box of the light/dark exploration test by 157%, indicating its anxiolytic activity. It decreased the duration of immobility in tail suspension test (suggesting its antidepressant activity), reduced stress-induced ulcers and reduced the convulsing action of PTZ and MES. The extract exhibited tendency to reduce the intensity of behavior mediated via serotonin and acetylcholine. The effect on DA- and noradrenaline-mediated behavior was not significant. In conclusion, the extract was found to possess nootropic, anxiolytic, antidepressant, anticonvulsant and antistress activity. Further studies are necessary to isolate the active principle responsible for the activities and to understand its mode of action. PMID:12895670

  13. DNA methylation functions as a critical regulator of Kir4.1 expression during CNS development

    PubMed Central

    Nwaobi, Sinifunanya E; Lin, Erica; Peramsetty, Sasank R; Olsen, Michelle L

    2014-01-01

    Kir4.1, a glial-specific K+ channel, is critical for normal CNS development. Studies utilizing both global and glial-specific knockout of Kir4.1 reveal abnormal CNS development with the loss of the channel. Specifically, Kir4.1 knockout animals are characterized by ataxia, severe hypomyelination, and early postnatal death. Additionally, Kir4.1 has emerged as a key player in several CNS diseases. Notably, decreased Kir4.1 protein expression occurs in several human CNS pathologies including CNS ischemic injury, spinal cord injury, epilepsy, ALS, and Alzheimer’s disease. Despite the emerging significance of Kir4.1 in normal and pathological conditions, its mechanisms of regulation are unknown. Here we report the first epigenetic regulation of a K+ channel in the CNS. Robust developmental upregulation of Kir4.1 expression in rats is coincident with reductions in DNA methylation of the Kir4.1 gene, KCNJ10. Chromatin immunoprecipitation reveals a dynamic interaction between KCNJ10 and DNA methyltransferase 1 during development. Finally, demethylation of the KCNJ10 promoter is necessary for transcription. These findings indicate DNA methylation is a key regulator of Kir4.1 transcription. Given the essential role of Kir4.1 in normal CNS development, understanding the regulation of this K+ channel is critical to understanding normal glial biology. PMID:24415225

  14. The role of the blood-CNS barrier in CNS disorders and their treatment.

    PubMed

    Palmer, Alan M

    2010-01-01

    The physical barrier between blood and the CNS (the blood-brain barrier, the blood-spinal cord barrier and the blood-CSF barrier) protects the CNS from both toxic and pathogenic agents in the blood. It is now clear that disruption of the blood-CNS barrier plays a key role in a number of CNS disorders, particularly those associated with neurodegeneration. Such disruption is inevitably accompanied by inflammatory change, as immune cells and immune mediators gain access to the brain or spinal cord. The blood-CNS barrier also presents a major obstacle for potential CNS medicines. Robust methods to assess CNS permeation are therefore essential for CNS drug discovery, particularly when brain pharmacokinetics are taken into account and especially when such measures are linked to neurochemical, physiological, behavioural or neuroimaging readouts of drug action. Drug candidates can be successfully designed to cross the blood-CNS barrier, but for those that can't there is the possibility of entry with a delivery system that facilitates the movement of drug candidate across the blood-CNS barrier. PMID:19664711

  15. Expression of the Homeobox Gene HOXA9 in Ovarian Cancer Induces Peritoneal Macrophages to Acquire an M2 Tumor-Promoting Phenotype

    PubMed Central

    Ko, Song Yi; Ladanyi, Andras; Lengyel, Ernst; Naora, Honami

    2015-01-01

    Tumor-associated macrophages (TAMs) exhibit an M2 macrophage phenotype that suppresses anti-tumor immune responses and often correlates with poor outcomes in patients with cancer. Patients with ovarian cancer frequently present with peritoneal carcinomatosis, but the mechanisms that induce naïve peritoneal macrophages into TAMs are poorly understood. In this study, we found an increased abundance of TAMs in mouse i.p. xenograft models of ovarian cancer that expressed HOXA9, a homeobox gene that is associated with poor prognosis in patients with ovarian cancer. HOXA9 expression in ovarian cancer cells stimulated chemotaxis of peritoneal macrophages and induced macrophages to acquire TAM-like features. These features included induction of the M2 markers, CD163 and CD206, and the immunosuppressive cytokines, IL-10 and chemokine ligand 17, and down-regulation of the immunostimulatory cytokine, IL-12. HOXA9-mediated induction of TAMs was primarily due to the combinatorial effects of HOXA9-induced, tumor-derived transforming growth factor-β2 and chemokine ligand 2 levels. High HOXA9 expression in clinical specimens of ovarian cancer was strongly associated with increased abundance of TAMs and intratumoral T-regulatory cells and decreased abundance of CD8+ tumor-infiltrating lymphocytes. Levels of immunosuppressive cytokines were also elevated in ascites fluid of patients with tumors that highly expressed HOXA9. HOXA9 may, therefore, stimulate ovarian cancer progression by promoting an immunosuppressive microenvironment via paracrine effects on peritoneal macrophages. PMID:24332016

  16. Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL.

    PubMed

    Savage, Kerry J; Slack, Graham W; Mottok, Anja; Sehn, Laurie H; Villa, Diego; Kansara, Roopesh; Kridel, Robert; Steidl, Christian; Ennishi, Daisuke; Tan, King L; Ben-Neriah, Susana; Johnson, Nathalie A; Connors, Joseph M; Farinha, Pedro; Scott, David W; Gascoyne, Randy D

    2016-05-01

    Dual expression of MYC and BCL2 by immunohistochemistry (IHC) is associated with poor outcome in diffuse large B-cell lymphoma (DLBCL). Dual translocation of MYC and BCL2, so-called "double-hit lymphoma," has been associated with a high risk of central nervous system (CNS) relapse; however, the impact of dual expression of MYC and BCL2 (dual expressers) on the risk of CNS relapse remains unknown. Pretreatment formalin-fixed paraffin-embedded DLBCL biopsies derived from patients subsequently treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were assembled on tissue microarrays from 2 studies and were evaluated for expression of MYC and BCL2 by IHC. In addition, cell of origin was determined by IHC and the Lymph2Cx gene expression assay in a subset of patients. We identified 428 patients who met the inclusion criteria. By the recently described CNS risk score (CNS-International Prognostic Index [CNS-IPI]), 34% were low risk (0 to 1), 45% were intermediate risk (2 to 3), and 21% were high risk (4 or greater). With a median follow-up of 6.8 years, the risk of CNS relapse was higher in dual expressers compared with non-dual expressers (2-year risk, 9.7% vs 2.2%; P = .001). Patients with activated B-cell or non-germinal center B-cell type DLBCL also had an increased risk of CNS relapse. However, in multivariate analysis, only dual expresser status and CNS-IPI were associated with CNS relapse. Dual expresser MYC(+) BCL2(+) DLBCL defines a group at high risk of CNS relapse, independent of CNS-IPI score and cell of origin. Dual expresser status may help to identify a high-risk group who should undergo CNS-directed evaluation and consideration of prophylactic strategies. PMID:26834242

  17. Treatment Option Overview (Primary CNS Lymphoma)

    MedlinePlus

    ... large vein near the heart. Having a weakened immune system may increase the risk of developing primary CNS ... immunodeficiency syndrome (AIDS) or other disorders of the immune system or who have had a kidney transplant . For ...

  18. Treatment Options for Primary CNS Lymphoma

    MedlinePlus

    ... large vein near the heart. Having a weakened immune system may increase the risk of developing primary CNS ... immunodeficiency syndrome (AIDS) or other disorders of the immune system or who have had a kidney transplant . For ...

  19. Air Pollution: Mechanisms of Neuroinflammation & CNS Disease

    PubMed Central

    Block, Michelle L.; Calderón-Garcidueñas, Lilian

    2009-01-01

    Emerging evidence implicates air pollution as a chronic source of neuroinflammation, reactive oxygen species (ROS), and neuropathology instigating central nervous system (CNS) disease. Stroke incidence, and Alzheimer’s and Parkinson’s disease pathology are linked to air pollution. Recent reports reveal that air pollution components reach the brain. Further, systemic effects known to impact lung and cardiovascular disease also impinge upon CNS health. While mechanisms driving air pollution-induced CNS pathology are poorly understood, new evidence suggests that activation of microglia and changes in the blood brain barrier may be key to this process. Here, we summarize recent findings detailing the mechanisms through which air pollution reaches the brain and activates the resident innate immune response to become a chronic source of pro-inflammatory factors and ROS culpable in CNS disease. PMID:19716187

  20. Neurotrauma and Inflammation: CNS and PNS Responses

    PubMed Central

    Mietto, Bruno Siqueira; Mostacada, Klauss; Martinez, Ana Maria Blanco

    2015-01-01

    Traumatic injury to the central nervous system (CNS) or the peripheral nervous system (PNS) triggers a cascade of events which culminate in a robust inflammatory reaction. The role played by inflammation in the course of degeneration and regeneration is not completely elucidated. While, in peripheral nerves, the inflammatory response is assumed to be essential for normal progression of Wallerian degeneration and regeneration, CNS trauma inflammation is often associated with poor recovery. In this review, we discuss key mechanisms that trigger the inflammatory reaction after nervous system trauma, emphasizing how inflammations in both CNS and PNS differ from each other, in terms of magnitude, cell types involved, and effector molecules. Knowledge of the precise mechanisms that elicit and maintain inflammation after CNS and PNS tissue trauma and their effect on axon degeneration and regeneration is crucial for the identification of possible pharmacological drugs that can positively affect the tissue regenerative capacity. PMID:25918475

  1. Dynamics and mechanisms of CNS myelination.

    PubMed

    Bercury, Kathryn K; Macklin, Wendy B

    2015-02-23

    Vertebrate myelination is an evolutionary advancement essential for motor, sensory, and higher-order cognitive function. CNS myelin, a multilamellar differentiation of the oligodendrocyte plasma membrane, ensheaths axons to facilitate electrical conduction. Myelination is one of the most pivotal cell-cell interactions for normal brain development, involving extensive information exchange between differentiating oligodendrocytes and axons. The molecular mechanisms of myelination are discussed, along with new perspectives on oligodendrocyte plasticity and myelin remodeling of the developing and adult CNS. PMID:25710531

  2. CNS toxoplasmosis in an immunocompetent individual

    PubMed Central

    Ramachandran, Rajoo; Radhan, Prabhu; Anand, Rajamani; Subramanian, Ilanchezhian; Santosham, Roy; Sai, Venakata

    2015-01-01

    Toxoplasmosis is a serious and life-threatening disease in humans with a high prevalence in immunocompromised persons. The disease has a wide spectrum, depending on the immune status of the person. A CNS manifestation of toxoplasmosis in an immunocompetent person is very rare and often undetected. Our case of CNS toxoplasmosis in an immunocompetent person emphasizes the radiological diagnosis, which was further confirmed by advanced microbiology technique. PMID:27141248

  3. Community-acquired Acinetobacter meningitis in adults.

    PubMed

    Chang, W N; Lu, C H; Huang, C R; Chuang, Y C

    2000-01-01

    Community-acquired Acinetobacter meningitis in adults is an extremely rare infection of the central nervous system (CNS). Here we report one adult case of this rare CNS infection and review the clinical data of another seven cases reported in the English language literature. In total, eight patients (six men and two women) aged between 19 and 63 years were studied. The causative pathogen in our patient was Acinetobacter baumannii; in the other reported cases they were most likely Acinetobacter Iwoffii, Acinetobacter johnsonii, Acinetobacter junii, a genomic species 3 or 6. No underlying disease was found in seven of the eight cases and six of the eight patients acquired the infections before the age of 30 years. Fever and consciousness disturbance were the most common clinical manifestations. Waterhouse-Friderichsen syndrome (WFS) was found in two cases. Unlike the Acinetobacter strains found in nosocomial infections, the strain of Acinetobacter meningitis in the community-acquired case did not show multiple antibiotic resistance. Most adult patients with community-acquired Acinetobacter meningitis can be saved by timely therapy with appropriate antibiotics before deterioration of the systemic condition and impairment of consciousness. PMID:11139162

  4. Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery.

    PubMed

    Ghose, Arup K; Herbertz, Torsten; Hudkins, Robert L; Dorsey, Bruce D; Mallamo, John P

    2012-01-18

    The central nervous system (CNS) is the major area that is affected by aging. Alzheimer's disease (AD), Parkinson's disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood-brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å(2) (25-60 Å(2)), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740-970 Å(3), (vi) solvent accessible surface area of 460-580 Å(2), and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The

  5. Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery

    PubMed Central

    2011-01-01

    The central nervous system (CNS) is the major area that is affected by aging. Alzheimer’s disease (AD), Parkinson’s disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood–brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å2 (25–60 Å2), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740–970 Å3, (vi) solvent accessible surface area of 460–580 Å2, and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The

  6. Pannexin 2 protein expression is not restricted to the CNS

    PubMed Central

    Le Vasseur, Maxence; Lelowski, Jonathan; Bechberger, John F.; Sin, Wun-Chey; Naus, Christian C.

    2014-01-01

    Pannexins (Panx) are proteins homologous to the invertebrate gap junction proteins called innexins (Inx) and are traditionally described as transmembrane channels connecting the intracellular and extracellular compartments. Three distinct Panx paralogs (Panx1, Panx2 and Panx3) have been identified in vertebrates but previous reports on Panx expression and functionality focused primarily on Panx1 and Panx3 proteins. Several gene expression studies reported that Panx2 transcript is largely restricted to the central nervous system (CNS) hence suggesting that Panx2 might serve an important role in the CNS. However, the lack of suitable antibodies prevented the creation of a comprehensive map of Panx2 protein expression and Panx2 protein localization profile is currently mostly inferred from the distribution of its transcript. In this study, we characterized novel commercial monoclonal antibodies and surveyed Panx2 expression and distribution at the mRNA and protein level by real-time qPCR, Western blotting and immunofluorescence. Panx2 protein levels were readily detected in every tissue examined, even when transcriptional analysis predicted very low Panx2 protein expression. Furthermore, our results indicate that Panx2 transcriptional activity is a poor predictor of Panx2 protein abundance and does not correlate with Panx2 protein levels. Despite showing disproportionately high transcript levels, the CNS expressed less Panx2 protein than any other tissues analyzed. Additionally, we showed that Panx2 protein does not localize at the plasma membrane like other gap junction proteins but remains confined within cytoplasmic compartments. Overall, our results demonstrate that the endogenous expression of Panx2 protein is not restricted to the CNS and is more ubiquitous than initially predicted. PMID:25505382

  7. School Reentry for Children with Acquired Central Nervous Systems Injuries

    ERIC Educational Resources Information Center

    Carney, Joan; Porter, Patricia

    2009-01-01

    Onset of acquired central nervous system (CNS) injury during the normal developmental process of childhood can have impact on cognitive, behavioral, and motor function. This alteration of function often necessitates special education programming, modifications, and accommodations in the education setting for successful school reentry. Special…

  8. Differential Stability of PNS and CNS Nodal Complexes When Neuronal Neurofascin Is Lost

    PubMed Central

    Desmazieres, Anne; Zonta, Barbara; Zhang, Ao; Wu, Lai-Man N.; Sherman, Diane L.

    2014-01-01

    Fast, saltatory conduction in myelinated nerves requires the clustering of voltage-gated sodium channels (Nav) at nodes of Ranvier in a nodal complex. The Neurofascin (Nfasc) gene encodes neuronal Neurofascin 186 (Nfasc186) at the node and glial Neurofascin 155 at the paranode, and these proteins play a key role in node assembly. However, their role in the maintenance and stability of the node is less well understood. Here we show that by inducible ablation of Nfasc in neurons in adult mice, Nfasc186 expression is reduced by >99% and 94% at PNS and CNS nodes, respectively. Gliomedin and NrCAM at PNS and brevican at CNS nodes are largely lost with neuronal neurofascin; however, Nav at nodes of Ranvier persist, albeit with ∼40% reduction in expression levels. βIV Spectrin, ankyrin G, and, to a lesser extent, the β1 subunit of the sodium channel, are less affected at the PNS node than in the CNS. Nevertheless, there is a 38% reduction in PNS conduction velocity. Loss of Nfasc186 provokes CNS paranodal disorganization, but this does not contribute to loss of Nav. These results show that Nav at PNS nodes are still maintained in a nodal complex when neuronal neurofascin is depleted, whereas the retention of nodal Nav in the CNS, despite more extensive dissolution of the complex, suggests a supportive role for the partially disrupted paranodal axoglial junction in selectively maintaining Nav at the CNS node. PMID:24719087

  9. Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons

    NASA Technical Reports Server (NTRS)

    Kirkpatrick, L. L.; Witt, A. S.; Payne, H. R.; Shine, H. D.; Brady, S. T.

    2001-01-01

    Altered axon-Schwann cell interactions in PNS myelin-deficient Trembler mice result in changed axonal transport rates, neurofilament and microtubule-associated protein phosphorylation, neurofilament density, and microtubule stability. To determine whether PNS and CNS myelination have equivalent effects on axons, neurofilaments, and microtubules in CNS, myelin-deficient shiverer axons were examined. The genetic defect in shiverer is a deletion in the myelin basic protein (MBP) gene, an essential component of CNS myelin. As a result, shiverer mice have little or no compact CNS myelin. Slow axonal transport rates in shiverer CNS axons were significantly increased, in contrast to the slowing in demyelinated PNS nerves. Even more striking were substantial changes in the composition and properties of microtubules in shiverer CNS axons. The density of axonal microtubules is increased, reflecting increased expression of tubulin in shiverer, and the stability of microtubules is drastically reduced in shiverer axons. Shiverer transgenic mice with two copies of a wild-type myelin basic protein transgene have an intermediate level of compact myelin, making it possible to determine whether the actual level of compact myelin is an important regulator of axonal microtubules. Both increased microtubule density and reduced microtubule stability were still observed in transgenic mouse nerves, indicating that signals beyond synaptogenesis and the mere presence of compact myelin are required for normal regulation of the axonal microtubule cytoskeleton.

  10. Differential stability of PNS and CNS nodal complexes when neuronal neurofascin is lost.

    PubMed

    Desmazieres, Anne; Zonta, Barbara; Zhang, Ao; Wu, Lai-Man N; Sherman, Diane L; Brophy, Peter J

    2014-04-01

    Fast, saltatory conduction in myelinated nerves requires the clustering of voltage-gated sodium channels (Nav) at nodes of Ranvier in a nodal complex. The Neurofascin (Nfasc) gene encodes neuronal Neurofascin 186 (Nfasc186) at the node and glial Neurofascin 155 at the paranode, and these proteins play a key role in node assembly. However, their role in the maintenance and stability of the node is less well understood. Here we show that by inducible ablation of Nfasc in neurons in adult mice, Nfasc186 expression is reduced by >99% and 94% at PNS and CNS nodes, respectively. Gliomedin and NrCAM at PNS and brevican at CNS nodes are largely lost with neuronal neurofascin; however, Nav at nodes of Ranvier persist, albeit with ∼40% reduction in expression levels. βIV Spectrin, ankyrin G, and, to a lesser extent, the β1 subunit of the sodium channel, are less affected at the PNS node than in the CNS. Nevertheless, there is a 38% reduction in PNS conduction velocity. Loss of Nfasc186 provokes CNS paranodal disorganization, but this does not contribute to loss of Nav. These results show that Nav at PNS nodes are still maintained in a nodal complex when neuronal neurofascin is depleted, whereas the retention of nodal Nav in the CNS, despite more extensive dissolution of the complex, suggests a supportive role for the partially disrupted paranodal axoglial junction in selectively maintaining Nav at the CNS node. PMID:24719087

  11. Risk of CNS dissemination in extranodal lymphomas.

    PubMed

    Ferreri, Andrés J M

    2014-04-01

    Extranodal lymphomas constitute a heterogeneous group of malignancies, accounting for roughly 60% of all non-Hodgkin lymphomas. The extranodal organ where lymphomas arise is an important determining factor of biological, molecular, and aetio-pathogenic features, and of presentation, dissemination pattern, and outcome. An increased risk of CNS involvement, an uncommon but lethal event, has been suggested in some extranodal lymphomas, but the absolute risk is still debatable for most of these malignancies. This debate is because of the presence of selection biases and other confounding factors in related literature, which inevitably has led to conflicting recommendations. The identification of extranodal lymphomas at increased risk of CNS dissemination is an important unmet clinical need; affected patients could benefit from early CNS assessment by neuroimaging and cerebrospinal fluid analysis and adequate CNS prophylaxis, avoiding unnecessary prophylaxis and related toxicity in low-risk patients. This Review discusses relevant confounding factors and identifies high-risk extranodal lymphomas analysing histopathological category, involved organ, and other specific risk factors, which could be helpful for result interpretation and patient stratification in future clinical trials. Finally, a recommendation is provided for CNS-directed management of high-risk extranodal lymphoma patients in daily practice. PMID:24694639

  12. School reentry for children with acquired central nervous systems injuries.

    PubMed

    Carney, Joan; Porter, Patricia

    2009-01-01

    Onset of acquired central nervous system (CNS) injury during the normal developmental process of childhood can have impact on cognitive, behavioral, and motor function. This alteration of function often necessitates special education programming, modifications, and accommodations in the education setting for successful school reentry. Special education is not necessarily a special classroom, but an individualized set of educational needs, determined by a multidisciplinary school team, to promote educational success. The purpose of this article is to inform those pediatricians and pediatric allied health professionals treating children with CNS injury of the systems in place to support successful school reentry and their role in contributing to developing an appropriate educational plan. PMID:19489086

  13. CNS involvement in small noncleaved-cell lymphoma: is CNS disease per se a poor prognostic sign?

    PubMed

    Haddy, T B; Adde, M A; Magrath, I T

    1991-11-01

    Of 120 patients with small noncleaved-cell lymphoma who were entered sequentially on four National Cancer Institute (NCI) protocols, 29 (24%) had CNS involvement at some time in their clinical course. Seventeen had initial CNS involvement, and 12 developed CNS involvement at the time of first relapse. All 29 patients had extensive disease at presentation. The median serum lactate dehydrogenase (LDH) levels at presentation were 1,150 IU/L for patients with initial CNS involvement and 1,083 IU/L for patients with CNS involvement at relapse. CNS disease was significantly associated with serum LDH levels (P less than .0001), bone marrow involvement (P less than .0001), and jaw involvement (P = .018), but not involvement of the abdomen. There were nine long-term survivors among the 29 patients (31%). CNS disease did not appear to confer a worse prognosis on these patients than on patients without CNS involvement who had similar degrees of serum LDH elevation or who had bone marrow involvement, suggesting that extensive disease rather than CNS involvement was responsible for the poor prognosis. Event-free survival for patients with serum LDH levels above 500 IU/L was not different whether CNS disease was present or not (P = .29), nor was event-free survival different for patients with stage IV disease, whether CNS disease was present or not (P = .92). Although some patients had CNS radiation, there was no evidence that this was of therapeutic benefit. Intrathecal (IT) chemoprophylaxis effectively prevented spread to the CNS in patients without initial CNS involvement. Five of 18 patients (28%) who received no IT prophylaxis had CNS relapse (four isolated to the CNS), but only seven of the 85 patients (8%) who received IT prophylaxis had CNS relapse (two isolated to the CNS). The differences in overall and isolated CNS relapse rates were statistically significant (P = .034 and P = .008, respectively). PMID:1941056

  14. Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists.

    PubMed

    Joshi, Pramod; Anderson, Corey; Binch, Hayley; Hadida, Sabine; Yoo, Sanghee; Bergeron, Danielle; Decker, Caroline; terHaar, Ernst; Moore, Jonathan; Garcia-Guzman, Miguel; Termin, Andreas

    2014-02-01

    Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki=30 pM, IC50=1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties. PMID:24405707

  15. Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases.

    PubMed

    Bar-Or, Amit; Hintzen, Rogier Q; Dale, Russell C; Rostasy, Kevin; Brück, Wolfgang; Chitnis, Tanuja

    2016-08-30

    Elucidating pathophysiologic mechanisms underlying the spectrum of pediatric-onset CNS demyelinating diseases, particularly those that may distinguish multiple sclerosis (MS) from other entities, promises to both improve diagnostics and guide more-informed therapeutic decisions. Observations that pediatric- and adult-onset MS share the same genetic and environmental risk factors support the view that these conditions represent essentially the same illness manifesting at different ages. Nonetheless, special consideration must be given when CNS inflammation manifests in early life, at a time when multiple organs (including immune and nervous systems) are actively maturing. CSF analysis in pediatric-onset MS points to chronic CNS inflammation, supported by observations from limited pathologic material available for study. Emerging results implicate abnormalities in both effector and regulatory T cell subsets, and potentially immune senescence, in children with MS. Although CNS-directed antibodies (including antibodies recognizing myelin antigens; Kir4.1) can be documented in pediatric-onset MS, their pathophysiologic significance (as in adults) remains unclear. This is in contrast to the presence of serum and/or CSF antibodies recognizing aquaporin-4, which, when measured using validated cell-based assays, supports the diagnosis of a neuromyelitis optica spectrum disorder, distinct from MS. Presence of anti-myelin oligodendrocyte glycoprotein antibodies documented with similar cell-based assays may also be associated with pathophysiologically distinct disease phenotypes in children. The substantial impact of pediatric-onset MS on normal brain development and function underscores the importance of elucidating both the immunobiology and neurobiology of disease. Ongoing efforts are aimed at developing and validating biological measures that define pathophysiologically distinct monophasic and chronic forms of pediatric CNS demyelination. PMID:27572856

  16. N-Acetylaspartate in the CNS: From Neurodiagnostics to Neurobiology

    PubMed Central

    Moffett, John R.; Ross, Brian; Arun, Peethambaran; Madhavarao, Chikkathur N.; Namboodiri, M. A. A.

    2007-01-01

    The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research

  17. Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins.

    PubMed

    Montesinos-Rongen, Manuel; Purschke, Frauke G; Brunn, Anna; May, Caroline; Nordhoff, Eckhard; Marcus, Katrin; Deckert, Martina

    2015-08-01

    Primary lymphoma of the CNS (PCNSL) is a diffuse large B cell lymphoma confined to the CNS. To elucidate its peculiar organ tropism, we generated recombinant Abs (recAbs) identical to the BCR of 23 PCNSLs from immunocompetent patients. Although none of the recAbs showed self-reactivity upon testing with common autoantigens, they recognized 1547 proteins present on a large-scale protein microarray, indicating polyreactivity. Interestingly, proteins (GRINL1A, centaurin-α, BAIAP2) recognized by the recAbs are physiologically expressed by CNS neurons. Furthermore, 87% (20/23) of the recAbs, including all Abs derived from IGHV4-34 using PCNSL, recognized galectin-3, which was upregulated on microglia/macrophages, astrocytes, and cerebral endothelial cells upon CNS invasion by PCNSL. Thus, PCNSL Ig may recognize CNS proteins as self-Ags. Their interaction may contribute to BCR signaling with sustained NF-κB activation and, ultimately, may foster tumor cell proliferation and survival. These data may also explain, at least in part, the affinity of PCNSL cells for the CNS. PMID:26116512

  18. Hospital-acquired pneumonia

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000146.htm Hospital-acquired pneumonia To use the sharing features on this page, please enable JavaScript. Hospital-acquired pneumonia is an infection of the lungs ...

  19. Target Identification for CNS Diseases by Transcriptional Profiling

    PubMed Central

    Altar, C Anthony; Vawter, Marquis P; Ginsberg, Stephen D

    2008-01-01

    Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer’s disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to τ, amyloid-β precursor protein, and amyloid-β peptides (Aβ), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson’s disease (PD) include the ubiquitin–proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14

  20. Experimental Study of Stellar Reactions at CNS

    NASA Astrophysics Data System (ADS)

    Kubono, S.; Yamaguchi, H.; Wakabayashi, Y.; Amadio, G.; Hayakawa, S.; He, J. J.; Saito, A.; Teranishi, T.; Nishimura, S.; Fukunishi, N.; Iwasa, N.; Inafuku, K.; Kato, S.; Tanaka, M. H.; Fuchi, Y.; Moon, J. Y.; Kwon, K.; Lee, C. S.; Khiem, Le Hong; Chen, A.; Pearson, J.

    2006-11-01

    After a brief review on low-energy RI beam production technology, nuclear astrophysics programs at CNS are presented including a scope of the field in the Wako campus. The CRIB project involves a total development of the whole facility to maximize the low-energy RI beam intensities, including the ion source, the AVF cyclotron and the low-energy RI beam separator CRIB, Some recent nuclear astrophysics experiments performed with the RI beams were discussed, including the measurement of the 14O(α,p)17F reaction, the key stellar reaction for the onset of the high-temperature rp-process. The first experiment performed with a newly installed high-resolution magnetic spectrograph PA of CNS was also presented. Collaboration possibilities for nuclear astrophysics in the RIKEN campus are also touched.

  1. VIIP: Central Nervous System (CNS) Modeling

    NASA Technical Reports Server (NTRS)

    Vera, Jerry; Mulugeta, Lealem; Nelson, Emily; Raykin, Julia; Feola, Andrew; Gleason, Rudy; Samuels, Brian; Ethier, C. Ross; Myers, Jerry

    2015-01-01

    Current long-duration missions to the International Space Station and future exploration-class missions beyond low-Earth orbit expose astronauts to increased risk of Visual Impairment and Intracranial Pressure (VIIP) syndrome. It has been hypothesized that the headward shift of cerebrospinal fluid (CSF) and blood in microgravity may cause significant elevation of intracranial pressure (ICP), which in turn may then induce VIIP syndrome through interaction with various biomechanical pathways. However, there is insufficient evidence to confirm this hypothesis. In this light, we are developing lumped-parameter models of fluid transport in the central nervous system (CNS) as a means to simulate the influence of microgravity on ICP. The CNS models will also be used in concert with the lumped parameter and finite element models of the eye described in the related IWS works submitted by Nelson et al., Feola et al. and Ethier et al.

  2. Interneuron Progenitor Transplantation to Treat CNS Dysfunction

    PubMed Central

    Chohan, Muhammad O.; Moore, Holly

    2016-01-01

    Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field. PMID:27582692

  3. Cerebral blood flow variations in CNS lupus

    SciTech Connect

    Kushner, M.J.; Tobin, M.; Fazekas, F.; Chawluk, J.; Jamieson, D.; Freundlich, B.; Grenell, S.; Freemen, L.; Reivich, M. )

    1990-01-01

    We studied the patterns of cerebral blood flow (CBF), over time, in patients with systemic lupus erythematosus and varying neurologic manifestations including headache, stroke, psychosis, and encephalopathy. For 20 paired xenon-133 CBF measurements, CBF was normal during CNS remissions, regardless of the symptoms. CBF was significantly depressed during CNS exacerbations. The magnitude of change in CBF varied with the neurologic syndrome. CBF was least affected in patients with nonspecific symptoms such as headache or malaise, whereas patients with encephalopathy or psychosis exhibited the greatest reductions in CBF. In 1 patient with affective psychosis, without clinical or CT evidence of cerebral ischemia, serial SPECT studies showed resolution of multifocal cerebral perfusion defects which paralleled clinical recovery.

  4. Experimental Study of Stellar Reactions at CNS

    SciTech Connect

    Kubono, S.; Yamaguchi, H.; Wakabayashi, Y.; Amadio, G.; Hayakawa, S.; He, J. J.; Saito, A.; Teranishi, T.; Nishimura, S.; Fukunishi, N.; Iwasa, N.; Inafuku, K.; Kato, S.; Tanaka, M. H.; Fuchi, Y.; Moon, J. Y.; Kwon, K.; Lee, C. S.; Khiem, Le Hong; Chen, A.

    2006-11-02

    After a brief review on low-energy RI beam production technology, nuclear astrophysics programs at CNS are presented including a scope of the field in the Wako campus. The CRIB project involves a total development of the whole facility to maximize the low-energy RI beam intensities, including the ion source, the AVF cyclotron and the low-energy RI beam separator CRIB, Some recent nuclear astrophysics experiments performed with the RI beams were discussed, including the measurement of the 14O({alpha},p)17F reaction, the key stellar reaction for the onset of the high-temperature rp-process. The first experiment performed with a newly installed high-resolution magnetic spectrograph PA of CNS was also presented. Collaboration possibilities for nuclear astrophysics in the RIKEN campus are also touched.

  5. Antiretroviral therapy CNS penetration and HIV-1–associated CNS disease

    PubMed Central

    Winston, A.; Walsh, J.; Post, F.; Porter, K.; Gazzard, B.; Fisher, M.; Leen, C.; Pillay, D.; Hill, T.; Johnson, M.; Gilson, R.; Anderson, J.; Easterbrook, P.; Bansi, L.; Orkin, C.; Ainsworth, J.; Palfreeman, A.; Gompels, M.; Phillips, A.N.; Sabin, C.A.

    2011-01-01

    Objective: The impact of different antiretroviral agents on the risk of developing or surviving CNS disease remains unknown. The aim of this study was to investigate whether using antiretroviral regimens with higher CNS penetration effectiveness (CPE) scores was associated with reduced incidence of CNS disease and improved survival in the UK Collaborative HIV Cohort (CHIC) Study. Methods: Adults without previous CNS disease, who commenced combination antiretroviral therapy (cART) between 1996 and 2008, were included (n = 22,356). Initial and most recent cART CPE scores were calculated. CNS diseases were HIV encephalopathy (HIVe), progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis (TOXO), and cryptococcal meningitis (CRYPTO). Incidence rates and overall survival were stratified by CPE score. A multivariable Poisson regression model was used to identify independent associations. Results: The median (interquartile range) CPE score for initial cART regimen increased from 7 (5–8) in 1996–1997 to 9 (8–10) in 2000–2001 and subsequently declined to 6 (7–8) in 2006–2008. Differences in gender, HIV acquisition risk group, and ethnicity existed between CPE score strata. A total of 251 subjects were diagnosed with a CNS disease (HIVe 80; TOXO 59; CRYPTO 56; PML 54). CNS diseases occurred more frequently in subjects prescribed regimens with CPE scores ≤4, and less frequently in those with scores ≥10; however, these differences were nonsignificant. Initial and most recent cART CPE scores ≤4 were independently associated with increased risk of death. Conclusion: Clinical status at time of commencing cART influences antiretroviral selection and CPE score. This information should be considered when utilizing CPE scores for retrospective analyses. PMID:21339496

  6. Histoplasmosis with Deep CNS Involvement: Case Presentation with Discussion and Literature Review

    PubMed Central

    Hariri, Omid R.; Minasian, Tanya; Quadri, Syed A.; Dyurgerova, Anya; Farr, Saman; Miulli, Dan E.; Siddiqi, Javed

    2015-01-01

    Central nervous system (CNS) histoplasmosis is rare and difficult to diagnose because it is often overlooked or mistaken for other pathologies due to its nonspecific symptoms. A 32-year-old Hispanic man with advanced acquired immunodeficiency virus presented with altered mental status and reported confusion for the past 3 months. He had a Glasgow Coma Scale of 12, repetitive nonfluent speech, and a disconjugate gaze with a right gaze preference. Lung computed tomography (CT) findings indicated a pulmonary histoplasmosis infection. Magnetic resonance imaging of the brain revealed a ring-enhancing lesion in the left caudate nucleus. A CT-guided left retroperitoneal node biopsy was performed and indicated a benign inflammatory process with organisms compatible with fungal yeast. Treatment with amphotericin B followed by itraconazole was initiated in spite of negative cerebrospinal fluid (CSF) cultures and proved effective in mitigating associated CNS lesions and resolving neurologic deficits. The patient was discharged 3 weeks later in stable condition. Six weeks later, his left basal ganglia mass decreased. Early recognition of symptoms and proper steps is key in improving outcomes of CNS histoplasmosis. Aggressive medical management is possible in the treatment of intracranial deep mass lesions, and disseminated histoplasmosis with CNS involvement can be appropriately diagnosed and treated, despite negative CSF and serology studies. PMID:26251798

  7. Are Microglial Cells the Regulators of Lymphocyte Responses in the CNS?

    PubMed Central

    Almolda, Beatriz; González, Berta; Castellano, Bernardo

    2015-01-01

    The infiltration of immune cells in the central nervous system is a common hallmark in different neuroinflammatory conditions. Accumulating evidence indicates that resident glial cells can establish a cross-talk with infiltrated immune cells, including T-cells, regulating their recruitment, activation and function within the CNS. Although the healthy CNS has been thought to be devoid of professional dendritic cells (DCs), numerous studies have reported the presence of a population of DCs in specific locations such as the meninges, choroid plexuses and the perivascular space. Moreover, the infiltration of DC precursors during neuroinflammatory situations has been proposed, suggesting a putative role of these cells in the regulation of lymphocyte activity within the CNS. On the other hand, under specific circumstances, microglial cells are able to acquire a phenotype of DC expressing a wide range of molecules that equip these cells with all the necessary machinery for communication with T-cells. In this review, we summarize the current knowledge on the expression of molecules involved in the cross-talk with T-cells in both microglial cells and DCs and discuss the potential contribution of each of these cell populations on the control of lymphocyte function within the CNS. PMID:26635525

  8. Agile delivery of protein therapeutics to CNS.

    PubMed

    Yi, Xiang; Manickam, Devika S; Brynskikh, Anna; Kabanov, Alexander V

    2014-09-28

    A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics. PMID:24956489

  9. Histamine and Immune Biomarkers in CNS Disorders

    PubMed Central

    Cacabelos, Ramón; Torrellas, Clara; Fernández-Novoa, Lucía; López-Muñoz, Francisco

    2016-01-01

    Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer's disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death. PMID:27190492

  10. Agile Delivery of Protein Therapeutics to CNS

    PubMed Central

    Yi, Xiang; Manickam, Devika S.; Brynskikh, Anna; Kabanov, Alexander V.

    2014-01-01

    A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics. PMID:24956489

  11. A R2R3 type MYB transcription factor is involved in the cold regulation of CBF genes and in acquired freezing tolerance.

    PubMed

    Agarwal, Manu; Hao, Yujin; Kapoor, Avnish; Dong, Chun-Hai; Fujii, Hiroaki; Zheng, Xianwu; Zhu, Jian-Kang

    2006-12-01

    Cold temperatures trigger the expression of the CBF family of transcription factors, which in turn activate many downstream genes that confer freezing tolerance to plants. It has been shown previously that the cold regulation of CBF3 involves an upstream bHLH-type transcription factor, ICE1. ICE1 binds to the Myc recognition sequences in the CBF3 promoter. Apart from Myc recognition sequences, CBF promoters also have Myb recognition sequences. We report here that the Arabidopsis MYB15 is involved in cold-regulation of CBF genes and in the development of freezing tolerance. The MYB15 gene transcript is up-regulated by cold stress. The MYB15 protein interacts with ICE1 and binds to Myb recognition sequences in the promoters of CBF genes. Overexpression of MYB15 results in reduced expression of CBF genes whereas its loss-of-function leads to increased expression of CBF genes in the cold. The myb15 mutant plants show increased tolerance to freezing stress whereas its overexpression reduces freezing tolerance. Our results suggest that MYB15 is part of a complex network of transcription factors controlling the expression of CBFs and other genes in response to cold stress. PMID:17015446

  12. Progressive multifocal leukoencephalopathy occurring with the acquired immune deficiency syndrome.

    PubMed

    England, J D; Hsu, C Y; Garen, P D; Goust, J M; Biggs, P J

    1984-08-01

    A 33-year-old homosexual man with symptoms and signs of a focal brain process was subsequently found to have an acquired immune deficiency syndrome (AIDS) with biopsy-proven progressive multifocal leukoencephalopathy. This report reemphasizes the association of progressive multifocal leukoencephalopathy with AIDS and probably is best viewed as another example of an opportunistic CNS infection complicating deficient cell-mediated immunity. PMID:6540476

  13. Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.

    PubMed

    Vidadala, Rama Subba Rao; Rivas, Kasey L; Ojo, Kayode K; Hulverson, Matthew A; Zambriski, Jennifer A; Bruzual, Igor; Schultz, Tracey L; Huang, Wenlin; Zhang, Zhongsheng; Scheele, Suzanne; DeRocher, Amy E; Choi, Ryan; Barrett, Lynn K; Siddaramaiah, Latha Kallur; Hol, Wim G J; Fan, Erkang; Merritt, Ethan A; Parsons, Marilyn; Freiberg, Gail; Marsh, Kennan; Kempf, Dale J; Carruthers, Vern B; Isoherranen, Nina; Doggett, J Stone; Van Voorhis, Wesley C; Maly, Dustin J

    2016-07-14

    New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy. PMID:27309760

  14. Histamine pharmacology and new CNS drug targets.

    PubMed

    Tiligada, Ekaterini; Kyriakidis, Konstantinos; Chazot, Paul L; Passani, M Beatrice

    2011-12-01

    During the last decade, the identification of a number of novel drug targets led to the development of promising new compounds which are currently under evaluation for their therapeutic prospective in CNS related disorders. Besides the established pleiotropic regulatory functions in the periphery, the interest in the potential homeostatic role of histamine in the brain was revived following the identification of H(3) and H(4) receptors some years ago. Complementing classical CNS pharmacology, the development of selective histamine receptor agonists, antagonists, and inverse agonists provides the lead for the potential exploitation of the histaminergic system in the treatment of brain pathologies. Although no CNS disease entity has been associated directly to brain histamine dysfunction until now, the H(3) receptor is recognized as a drug target for neuropathic pain, sleep-wake disorders, including narcolepsy, and cognitive impairment associated with attention deficit hyperactivity disorder, schizophrenia, Alzheimer's, or Parkinson's disease, while the first H(3) receptor ligands have already entered phase I-III clinical trials. Interestingly, the localization of the immunomodulatory H(4) receptor in the nervous system exposes attractive perspectives for the therapeutic exploitation of this new drug target in neuroimmunopharmacology. This review focuses on a concise presentation of the current "translational research" approach that exploits the latest advances in histamine pharmacology for the development of beneficial drug targets for the treatment of neuronal disorders, such as neuropathic pain, cognitive, and sleep-wake pathologies. Furthermore, the role of the brain histaminergic system(s) in neuroprotection and neuroimmunology/inflammation remains a challenging research area that is currently under consideration. PMID:22070192

  15. Ex vivo generated natural killer cells acquire typical natural killer receptors and display a cytotoxic gene expression profile similar to peripheral blood natural killer cells.

    PubMed

    Lehmann, Dorit; Spanholtz, Jan; Osl, Markus; Tordoir, Marleen; Lipnik, Karoline; Bilban, Martin; Schlechta, Bernhard; Dolstra, Harry; Hofer, Erhard

    2012-11-01

    Ex vivo differentiation systems of natural killer (NK) cells from CD34+ hematopoietic stem cells are of potential importance for adjuvant immunotherapy of cancer. Here, we analyzed ex vivo differentiation of NK cells from cord blood-derived CD34+ stem cells by gene expression profiling, real-time RT-PCR, flow cytometry, and functional analysis. Additionally, we compared the identified characteristics to peripheral blood (PB) CD56(bright) and CD56(dim) NK cells. The data show sequential expression of CD56 and the CD94 and NKG2 receptor chains during ex vivo NK cell development, resulting finally in the expression of a range of genes with partial characteristics of CD56(bright) and CD56(dim) NK cells from PB. Expression of characteristic NK cell receptors and cytotoxic genes was mainly found within the predominant ex vivo generated population of NKG2A+ NK cells, indicating the importance of NKG2A expression during NK cell differentiation and maturation. Furthermore, despite distinct phenotypic characteristics, the detailed analysis of cytolytic genes expressed within the ex vivo differentiated NK cells revealed a pattern close to CD56(dim) NK cells. In line with this finding, ex vivo generated NK cells displayed potent cytotoxicity. This supports that the ex vivo differentiation system faithfully reproduces major steps of the differentiation of NK cells from their progenitors, constitutes an excellent model to study NK cell differentiation, and is valuable to generate large-scale NK cells appropriate for immunotherapy. PMID:22571679

  16. Acquired reactive perforating collagenosis.

    PubMed

    Basak, P Y; Turkmen, C

    2001-01-01

    Acquired perforating disorder has been recognized as an uncommon distinct dermatosis in which altered collagen is eliminated through the epidermis. Several disorders accompanied by itching and scratching were reported to be associated with reactive perforating collagenosis. A 67-year-old white woman diagnosed as acquired reactive perforating collagenosis with poorly controlled diabetes mellitus and congestive cardiac failure is presented. PMID:11525959

  17. Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet-induced) and genetic (yellow agouti) obesity.

    PubMed Central

    Mizuno, T M; Bergen, H; Funabashi, T; Kleopoulos, S P; Zhong, Y G; Bauman, W A; Mobbs, C V

    1996-01-01

    Mutations in the obese (ob) gene lead to obesity. This gene has been recently cloned, but the factors regulating its expression have not been elucidated. To address the regulation of the ob gene with regard to body weight and nutritional factors, Northern blot analysis was used to assess ob mRNA in adipose tissue from mice [lean, obese due to diet, or genetically (yellow agouti) obese] under different nutritional conditions. ob mRNA was elevated in both forms of obesity, compared to lean controls, correlated with elevations in plasma insulin and body weight, but not plasma glucose. In lean C57BL/6J mice, but not in mice with diet-induced obesity, ob mRNA decreased after a 48-hr fast. Similarly, in lean C57BL/6J controls, but not in obese yellow mice, i.p. glucose injection significantly increased ob mRNA. For up to 30 min after glucose injection, ob mRNA in lean mice significantly correlated with plasma glucose, but not with plasma insulin. In a separate study with only lean mice, ob mRNA was inhibited >90% by fasting, and elevated approximately 2-fold 30 min after i.p. injection of either glucose or insulin. These results suggest that in lean animals glucose and insulin enhance ob gene expression. In contrast to our results in lean mice, in obese animals ob mRNA is elevated and relatively insensitive to nutritional state, possibly due to chronic exposure to elevated plasma insulin and/or glucose. Images Fig. 1 Fig. 4 PMID:8622953

  18. Evolutionary diversification of the BetaM interactome acquired through co-option of the ATP1B4 gene in placental mammals

    PubMed Central

    Korneenko, Tatyana V.; Pestov, Nikolay B.; Ahmad, Nisar; Okkelman, Irina A.; Dmitriev, Ruslan I.; Shakhparonov, Mikhail I.; Modyanov, Nikolai N.

    2016-01-01

    ATP1B4 genes represent a rare instance of orthologous vertebrate gene co-option that radically changed properties of the encoded BetaM proteins, which function as Na,K-ATPase subunits in lower vertebrates and birds. Eutherian BetaM has lost its ancestral function and became a muscle-specific resident of the inner nuclear membrane. Our earlier work implicated BetaM in regulation of gene expression through direct interaction with the transcriptional co-regulator SKIP. To gain insight into evolution of BetaM interactome we performed expanded screening of eutherian and avian cDNA libraries using yeast-two-hybrid and split-ubiquitin systems. The inventory of identified BetaM interactors includes lamina-associated protein LAP-1, myocyte nuclear envelope protein Syne1, BetaM itself, heme oxidases HMOX1 and HMOX2; transcription factor LZIP/CREB3, ERGIC3, PHF3, reticulocalbin-3, and β-sarcoglycan. No new interactions were found for chicken BetaM and human Na,K-ATPase β1, β2 and β3 isoforms, indicating the uniqueness of eutherian BetaM interactome. Analysis of truncated forms of BetaM indicates that residues 72-98 adjacent to the membrane in nucleoplasmic domain are important for the interaction with SKIP. These findings demonstrate that evolutionary alterations in structural and functional properties of eutherian BetaM proteins are associated with the increase in its interactome complexity. PMID:26939788

  19. Evolutionary diversification of the BetaM interactome acquired through co-option of the ATP1B4 gene in placental mammals.

    PubMed

    Korneenko, Tatyana V; Pestov, Nikolay B; Ahmad, Nisar; Okkelman, Irina A; Dmitriev, Ruslan I; Shakhparonov, Mikhail I; Modyanov, Nikolai N

    2016-01-01

    ATP1B4 genes represent a rare instance of orthologous vertebrate gene co-option that radically changed properties of the encoded BetaM proteins, which function as Na,K-ATPase subunits in lower vertebrates and birds. Eutherian BetaM has lost its ancestral function and became a muscle-specific resident of the inner nuclear membrane. Our earlier work implicated BetaM in regulation of gene expression through direct interaction with the transcriptional co-regulator SKIP. To gain insight into evolution of BetaM interactome we performed expanded screening of eutherian and avian cDNA libraries using yeast-two-hybrid and split-ubiquitin systems. The inventory of identified BetaM interactors includes lamina-associated protein LAP-1, myocyte nuclear envelope protein Syne1, BetaM itself, heme oxidases HMOX1 and HMOX2; transcription factor LZIP/CREB3, ERGIC3, PHF3, reticulocalbin-3, and β-sarcoglycan. No new interactions were found for chicken BetaM and human Na,K-ATPase β1, β2 and β3 isoforms, indicating the uniqueness of eutherian BetaM interactome. Analysis of truncated forms of BetaM indicates that residues 72-98 adjacent to the membrane in nucleoplasmic domain are important for the interaction with SKIP. These findings demonstrate that evolutionary alterations in structural and functional properties of eutherian BetaM proteins are associated with the increase in its interactome complexity. PMID:26939788

  20. Electrophysiological CNS-processes related to associative learning in humans.

    PubMed

    Christoffersen, Gert R J; Schachtman, Todd R

    2016-01-01

    The neurophysiology of human associative memory has been studied with electroencephalographic techniques since the 1930s. This research has revealed that different types of electrophysiological processes in the human brain can be modified by conditioning: sensory evoked potentials, sensory induced gamma-band activity, periods of frequency-specific waves (alpha and beta waves, the sensorimotor rhythm and the mu-rhythm) and slow cortical potentials. Conditioning of these processes has been studied in experiments that either use operant conditioning or repeated contingent pairings of conditioned and unconditioned stimuli (classical conditioning). In operant conditioning, the appearance of a specific brain process is paired with an external stimulus (neurofeedback) and the feedback enables subjects to obtain varying degrees of control of the CNS-process. Such acquired self-regulation of brain activity has found practical uses for instance in the amelioration of epileptic seizures, Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). It has also provided communicative means of assistance for tetraplegic patients through the use of brain computer interfaces. Both extra and intracortically recorded signals have been coupled with contingent external feedback. It is the aim for this review to summarize essential results on all types of electromagnetic brain processes that have been modified by classical or operant conditioning. The results are organized according to type of conditioned EEG-process, type of conditioning, and sensory modalities of the conditioning stimuli. PMID:26367470

  1. Plant sterols: Friend or foe in CNS disorders?

    PubMed

    Vanmierlo, Tim; Bogie, Jeroen F J; Mailleux, Jo; Vanmol, Jasmine; Lütjohann, Dieter; Mulder, Monique; Hendriks, Jerome J A

    2015-04-01

    In mammals, the central nervous system (CNS) is the most cholesterol rich organ by weight. Cholesterol metabolism is tightly regulated in the CNS and all cholesterol available is synthesized in situ. Deficits in cholesterol homeostasis at the level of synthesis, transport, or catabolism result in severe disorders featured by neurological disability. Recent studies indicate that a disturbed cholesterol metabolism is involved in CNS disorders, such as Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In contrast to circulating cholesterol, dietary plant sterols, can cross the blood-brain barrier and accumulate in the membranes of CNS cells. Plant sterols are well-known for their ability to lower circulating cholesterol levels. The finding that they gain access to the CNS has fueled research focusing on the physiological roles of plant sterols in the healthy and diseased CNS. To date, both beneficial and detrimental effects of plant sterols on CNS disorders are defined. In this review, we discuss recent findings regarding the impact of plant sterols on homeostatic and pathogenic processes in the CNS, and elaborate on the therapeutic potential of plant sterols in CNS disorders. PMID:25623279

  2. Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic.

    PubMed

    Mi, Sha; Pepinsky, R Blake; Cadavid, Diego

    2013-07-01

    LINGO-1 is a leucine-rich repeat and Ig domain-containing, Nogo receptor interacting protein, selectively expressed in the CNS on both oligodendrocytes and neurons. Its expression is developmentally regulated, and is upregulated in CNS diseases and injury. In animal models, LINGO-1 expression is upregulated in rat spinal cord injury, experimental autoimmune encephalomyelitis, 6-hydroxydopamine neurotoxic lesions and glaucoma models. In humans, LINGO-1 expression is increased in oligodendrocyte progenitor cells from demyelinated white matter of multiple sclerosis post-mortem samples, and in dopaminergic neurons from Parkinson's disease brains. LINGO-1 negatively regulates oligodendrocyte differentiation and myelination, neuronal survival and axonal regeneration by activating ras homolog gene family member A (RhoA) and inhibiting protein kinase B (Akt) phosphorylation signalling pathways. Across diverse animal CNS disease models, targeted LINGO-1 inhibition promotes neuron and oligodendrocyte survival, axon regeneration, oligodendrocyte differentiation, remyelination and functional recovery. The targeted inhibition of LINGO-1 function presents a novel therapeutic approach for the treatment of CNS diseases. PMID:23681979

  3. Flipping the transcriptional switch from myelin inhibition to axon growth in the CNS

    PubMed Central

    Carmel, Jason B.; Young, Wise; Hart, Ronald P.

    2015-01-01

    Poor regeneration of severed axons in the central nervous system (CNS) limits functional recovery. Regeneration failure involves interplay of inhibitory environmental elements and the growth state of the neuron. To find internal changes in gene expression that might overcome inhibitory environmental cues, we compared several paradigms that allow growth in the inhibitory environment. Conditions that allow axon growth by axotomized and cultured dorsal root ganglion (DRG) neurons on CNS myelin include immaturity (the first few postnatal days), high levels of cyclic adenosine mono phosphate (cAMP), and conditioning with a peripheral nerve lesion before explant. This shift from inhibition to growth depends on transcription. Seeking to understand the transcriptome changes that allow axon growth in the CNS, we collaborated with the Marie Filbin laboratory to identify several mRNAs that are functionally relevant, as determined by gain- and loss-of-function studies. In this Perspective, we review evidence from these experiments and discuss the merits of comparing multiple regenerative paradigms to identify a core transcriptional program for CNS axon regeneration. PMID:26236189

  4. Peripheral monocytes are functionally altered and invade the CNS in ALS patients.

    PubMed

    Zondler, Lisa; Müller, Kathrin; Khalaji, Samira; Bliederhäuser, Corinna; Ruf, Wolfgang P; Grozdanov, Veselin; Thiemann, Meinolf; Fundel-Clemes, Katrin; Freischmidt, Axel; Holzmann, Karlheinz; Strobel, Benjamin; Weydt, Patrick; Witting, Anke; Thal, Dietmar R; Helferich, Anika M; Hengerer, Bastian; Gottschalk, Kay-Eberhard; Hill, Oliver; Kluge, Michael; Ludolph, Albert C; Danzer, Karin M; Weishaupt, Jochen H

    2016-09-01

    Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease affecting primarily the upper and lower motor neurons. A common feature of all ALS cases is a well-characterized neuroinflammatory reaction within the central nervous system (CNS). However, much less is known about the role of the peripheral immune system and its interplay with CNS resident immune cells in motor neuron degeneration. Here, we characterized peripheral monocytes in both temporal and spatial dimensions of ALS pathogenesis. We found the circulating monocytes to be deregulated in ALS regarding subtype constitution, function and gene expression. Moreover, we show that CNS infiltration of peripheral monocytes correlates with improved motor neuron survival in a genetic ALS mouse model. Furthermore, application of human immunoglobulins or fusion proteins containing only the human Fc, but not the Fab antibody fragment, increased CNS invasion of peripheral monocytes and delayed the disease onset. Our results underline the importance of peripheral monocytes in ALS pathogenesis and are in agreement with a protective role of monocytes in the early phase of the disease. The possibility to boost this beneficial function of peripheral monocytes by application of human immunoglobulins should be evaluated in clinical trials. PMID:26910103

  5. A horizontally acquired group II intron in the chloroplast psbA gene of a psychrophilic Chlamydomonas: In vitro self-splicing and genetic evidence for maturase activity

    PubMed Central

    ODOM, OBED W.; SHENKENBERG, DAVID L.; GARCIA, JOSHUA A.; HERRIN, DAVID L.

    2004-01-01

    The majority of known group II introns are from chloroplast genomes, yet the first self-splicing group II intron from a chloroplast gene was reported only recently, from the psbA gene of the euglenoid, Euglena myxocylindracea. Herein, we describe a large (2.6-kb) group II intron from the psbA gene (psbA1) of a psychrophilic Chlamydomonas sp. from Antarctica that self-splices accurately in vitro. Remarkably, this intron, which also encodes an ORF with putative reverse transcriptase, maturase, and endonuclease domains, is in the same location, and is related to the E. myxocylindracea intron, as well as to group IIB2 introns from cyanobacteria. In vitro self-splicing of Chs.psbA1 occurred via a lariat, and required Mg2+ (>12 mM) and NH4+. Self-splicing was improved by deleting most of the ORF and by using pre-RNAs directly from transcription reactions, suggestive of a role for folding during transcription. Self-splicing of Chs.psbA1 pre-RNAs showed temperature optima of ~44°C, but with a broad shoulder on the low side of the peak; splicing was nearly absent at 50°C, indicative of thermolability. Splicing of wild-type Chs.psbA1 also occurred in Escherichia coli, but not when the ORF was disrupted by mutations, providing genetic evidence that it has maturase activity. This work provides the first description of a ribozyme from a psychrophilic organism. It also appears to provide a second instance of interkingdom horizontal transfer of this group IIB2 intron (or a close relative) from cyanobacteria to chloroplasts. PMID:15208445

  6. Gasmin (BV2-5), a polydnaviral-acquired gene in Spodoptera exigua. Trade-off in the defense against bacterial and viral infections.

    PubMed

    Gasmi, Laila; Jakubowska, Agata K; Herrero, Salvador

    2016-03-01

    Thousands of Hymenopteran endoparasitoids have developed a unique symbiotic relationship with viruses named polydnavirus (PDVs). These viruses immunocompromise the lepidopteran host allowing the survival of the wasp eggs. In a previous work, we have shown the horizontal transfer of some polydnaviral genes into the genome of the Lepidoptera, Spodoptera exigua. One of these genes, BV2-5 (named gasmin) interferes with actin polymerization, negatively affecting the multiplication of baculovirus in cell culture. In this work, we have focused in the study of the effect of Gasmin expression on different aspects of the baculovirus production. In addition, and since actin polymerization is crucial for phagocytosis, we have studied the effect of Gasmin expression on the larval interaction with bacterial pathogens. Over-expression of Gasmin on hemocytes significantly reduces their capacity to phagocytize the pathogenic bacteria Bacillus thuringiensis. According to these results, gasmin domestication negatively affects baculovirus replication, but increases larvae susceptibility to bacterial infections as pay off. Although the effect of Gasmin on the insect interaction with other pathogens or parasitoids remain unknown, the opposite effects described here could shape the biological history of this species based on the abundance of certain type of pathogens as suggested by the presence of truncated forms of this protein in several regions of the world. PMID:26658027

  7. Acquired Cystic Kidney Disease

    MedlinePlus

    ... a kidney transplant or blood-filtering treatments called dialysis. The cysts are more likely to develop in people who are on kidney dialysis. The chance of developing acquired cystic kidney disease ...

  8. Hospital-acquired pneumonia

    MedlinePlus

    ... tends to be more serious than other lung infections because: People in the hospital are often very sick and cannot fight off ... prevent pneumonia. Most hospitals have programs to prevent hospital-acquired infections.

  9. The odyssey of a young gene: structure-function studies in human glutamate dehydrogenases reveal evolutionary-acquired complex allosteric regulation mechanisms.

    PubMed

    Zaganas, Ioannis V; Kanavouras, Konstantinos; Borompokas, Nikolas; Arianoglou, Giovanna; Dimovasili, Christina; Latsoudis, Helen; Vlassi, Metaxia; Mastorodemos, Vasileios

    2014-01-01

    Mammalian glutamate dehydrogenase (GDH) catalyzes the reversible inter-conversion of glutamate to α-ketoglutarate and ammonia, interconnecting carbon skeleton and nitrogen metabolism. In addition, it functions as an energy switch by its ability to fuel the Krebs cycle depending on the energy status of the cell. As GDH lies at the intersection of several metabolic pathways, its activity is tightly regulated by several allosteric compounds that are metabolic intermediates. In contrast to other mammals that have a single GDH-encoding gene, humans and great apes possess two isoforms of GDH (hGDH1 and hGDH2, encoded by the GLUD1 and GLUD2 genes, respectively) with distinct regulation pattern, but remarkable sequence similarity (they differ, in their mature form, in only 15 of their 505 amino-acids). The GLUD2 gene is considered a very young gene, emerging from the GLUD1 gene through retro-position only recently (<23 million years ago). The new hGDH2 iso-enzyme, through random mutations and natural selection, is thought to have conferred an evolutionary advantage that helped its persistence through primate evolution. The properties of the two highly homologous human GDHs have been studied using purified recombinant hGDH1 and hGDH2 proteins obtained by expression of the corresponding cDNAs in Sf21 cells. According to these studies, in contrast to hGDH1 that maintains basal activity at 35-40 % of its maximal, hGDH2 displays low basal activity that is highly responsive to activation by rising levels of ADP and/or L-leucine which can also act synergistically. While hGDH1 is inhibited potently by GTP, hGDH2 shows remarkable GTP resistance. Furthermore, the two iso-enzymes are differentially inhibited by estrogens, polyamines and neuroleptics, and also differ in heat-lability. To elucidate the molecular mechanisms that underlie these different regulation patterns of the two iso-enzymes (and consequently the evolutionary adaptation of hGDH2 to a new functional role), we have

  10. Resistance to methicillin of coagulase-negative staphylococci (CNS) isolated from bovine mastitis.

    PubMed

    Bochniarz, M; Wawron, W; Szczubial, M

    2013-01-01

    The aim of this study was to determine the mechanisms of staphylococcal resistance to methicillin. CNS (n = 100 isolates) were prepared from the mammary inflammatory secretions of 86 cows from farms located in the Lublin region. Methicillin-resistant isolates constituted 20.0% of all CNS. Staphylococcus sciuri (n=8) and Staphylococcus xylosus (n=6) were most abundant, followed by Staphylococcus chromogenes (n=3), Staphylococcus haemolyticus (n=2) and Staphylococcus warned (n=1). The mecA gene was found in 50.0% of MRCNS (10.0% of all CNS isolates) belonging to two species: S. sciuri and S. xylosus. All mecA-positive isolates contained the protein of low affinity to penicillin (penicillin-binding protein 2a - PBP2a). The enzyme hydrolysing the beta-lactam ring in antibiotics was detected in 40.0% of MRCNS; 10.0% of MRCNS isolates were characterised by the presence of the mecA gene and ability to produce beta-lactamase. The remaining 20.0% of MRCNS isolates showing phenotypic resistance to methicillin were mecA gene-negative and were not able to produce beta-lactamase. PMID:24597303

  11. Engineering the CNS stem cell microenvironment

    PubMed Central

    Williams, Cicely A; Lavik, Erin B

    2010-01-01

    The loss of neural tissue underlies the symptomatology of several neurological insults of disparate etiology, including trauma, cerebrovascular insult and neurodegenerative disease. Restoration of damaged neural tissue through the use of exogenous or endogenous neural stem or progenitor cells is an enticing therapeutic option provided one can control their proliferation, migration and differentiation. Initial attempts at CNS tissue engineering relied on the intrinsic cellular properties of progenitor cells; however, it is now appreciated that the microenvironment surrounding the cells plays an indispensible role in regulating stem cell behavior. This article focuses on attempts to engineer the neural stem cell microenvironment by utilizing the major cellular components of the niche (endothelial cells, astrocytes and ependymal cells) and the extracellular matrix in which they are embedded. PMID:19903005

  12. CNS active O-linked glycopeptides

    PubMed Central

    Jones, Evan M.; Polt, Robin

    2015-01-01

    Naturally occurring glycopeptides and glycoproteins play important roles in biological processes. Glycosylation is one of the most common post-translational modifications in vivo. Glycopeptides are involved in cell signaling and sorting, providing cell surface markers for recognition. From the drug design and synthesis perspective, modification of a peptide through glycosylation results in increased bioavailability and bioactivity of glycopeptides in living systems with negligible toxicity of degradation products. Glycopeptide synthesis can be accomplished through incorporation of a glycosylated amino acid in solid phase peptide synthesis (SPPS) to form the desired peptide, or via incorporation of sugar-amino acid moieties. Additionally, research indicates that glycosylation increases penetration of the blood-brain barrier (BBB) by peptides, which may lead to novel therapeutics for neurological disorders. Recent applications of glycopeptides have focused on the in vivo central nervous system (CNS) effects after peripheral administration of centrally active peptides modified with various carbohydrates. PMID:26157795

  13. Uric acid as a CNS antioxidant.

    PubMed

    Bowman, Gene L; Shannon, Jackilen; Frei, Balz; Kaye, Jeffrey A; Quinn, Joseph F

    2010-01-01

    Oxidative damage is a consistent finding in a number of central nervous system (CNS) disorders. Uric acid (UA) is a potent hydrophilic antioxidant that is modified by diet and drug. Several lines of evidence suggest that plasma UA may modulate outcomes in neurologic disease, but little attention has been paid to CNS levels of UA. Our objective was to test the hypothesis that cerebrospinal fluid (CSF) UA is determined by plasma UA, modified by blood-brain barrier (BBB) integrity and associated with rate of cognitive decline in Alzheimer's disease (AD). Also, since UA and ascorbic acid may act as antioxidants for one another, we also explored a potential interaction between them in the brain. Thirty-two patients with mild to moderate AD (Mini-Mental Status Exam 19 +/- 5) participated in a longitudinal biomarker study for one year involving standardized clinical assessments. CSF and blood were collected at baseline for UA, ascorbic acid, and albumin. Cognitive measures were collected at baseline and again one year later. CSF UA was independent of age, gender, and AD severity. CSF and plasma UA were positively correlated (r=0.669, p=0.001) and BBB impairment was associated with higher CSF levels of UA (p=0.028). Neither plasma nor CSF UA reached significant association with rates of cognitive decline over 1 year. CSF UA and CSF ascorbic acid were positively correlated (r=0.388, p=0.001). The hypothesis that CSF UA is determined by plasma UA and BBB integrity is supported, as is the hypothesis that UA and ascorbic acid are associated in CSF but not plasma. Adequately powered prospective studies would help assess any role for UA in primary and secondary prevention of AD. PMID:20061611

  14. Neurobiology of microglial action in CNS injuries: receptor-mediated signaling mechanisms and functional roles

    PubMed Central

    Hu, Xiaoming; Liou, Anthony K.F.; Leak, Rehana K.; Xu, Mingyue; An, Chengrui; Suenaga, Jun; Shi, Yejie; Gao, Yanqin; Zheng, Ping; Chen, Jun

    2014-01-01

    Microglia are the first line of immune defense against central nervous system (CNS) injuries and disorders. These highly plastic cells play dualistic roles in neuronal injury and recovery and are known for their ability to assume diverse phenotypes. A broad range of surface receptors are expressed on microglia and mediate microglial ‘On’ or ‘Off’ responses to signals from other host cells as well as invading microorganisms. The integrated actions of these receptors result in tightly regulated biological functions, including cell mobility, phagocytosis, the induction of acquired immunity, and trophic factor/inflammatory mediator release. Over the last few years, significant advances have been made towards deciphering the signaling mechanisms related to these receptors and their specific cellular functions. In this review, we describe the current state of knowledge of the surface receptors involved in microglial activation, with an emphasis on their engagement of distinct functional programs and their roles in CNS injuries. It will become evident from this review that microglial homeostasis is carefully maintained by multiple counterbalanced strategies, including, but not limited to, ‘On’ and ‘Off’ receptor signaling. Specific regulation of theses microglial receptors may be a promising therapeutic strategy against CNS injuries. PMID:24923657

  15. Mosaic prophages with horizontally acquired genes account for the emergence and diversification of the globally disseminated M1T1 clone of Streptococcus pyogenes.

    PubMed

    Aziz, Ramy K; Edwards, Robert A; Taylor, William W; Low, Donald E; McGeer, Allison; Kotb, Malak

    2005-05-01

    The recrudescence of severe invasive group A streptococcal (GAS) diseases has been associated with relatively few strains, including the M1T1 subclone that has shown an unprecedented global spread and prevalence and high virulence in susceptible hosts. To understand its unusual epidemiology, we aimed to identify unique genomic features that differentiate it from the fully sequenced M1 SF370 strain. We constructed DNA microarrays from an M1T1 shotgun library and, using differential hybridization, we found that both M1 strains are 95% identical and that the 5% unique M1T1 clone sequences more closely resemble sequences found in the M3 strain, which is also associated with severe disease. Careful analysis of these unique sequences revealed three unique prophages that we named M1T1.X, M1T1.Y, and M1T1.Z. While M1T1.Y is similar to phage 370.3 of the M1-SF370 strain, M1T1.X and M1T1.Z are novel and encode the toxins SpeA2 and Sda1, respectively. The genomes of these prophages are highly mosaic, with different segments being related to distinct streptococcal phages, suggesting that GAS phages continue to exchange genetic material. Bioinformatic and phylogenetic analyses revealed a highly conserved open reading frame (ORF) adjacent to the toxins in 18 of the 21 toxin-carrying GAS prophages. We named this ORF paratox, determined its allelic distribution among different phages, and found linkage disequilibrium between particular paratox alleles and specific toxin genes, suggesting that they may move as a single cassette. Based on the conservation of paratox and other genes flanking the toxins, we propose a recombination-based model for toxin dissemination among prophages. We also provide evidence that a minor population of the M1T1 clonal isolates have exchanged their virulence module on phage M1T1.Y, replacing it with a different module identical to that found on a related M3 phage. Taken together, the data demonstrate that mosaicism of the GAS prophages has contributed to

  16. Leptomeningeal metastasis of primary central nervous system (CNS) neoplasms.

    PubMed

    Engelhard, Herbert H; Corsten, Luke A

    2005-01-01

    Leptomeningeal dissemination of primary CNS tumors varies widely by histologic subtype. In certain tumors including medulloblastoma, ependymoma, germ cell tumors, and primary CNS lymphoma, seeding of the cerebrospinal fluid space is a critical factor in determining stage, prognosis and appropriate therapy. Other tumor types, such as glioma, may have radiographic evidence of leptomeningeal metastases without clear impact on prognosis or therapy. PMID:16211884

  17. Microbial Induction of Vascular Pathology in the CNS

    PubMed Central

    Kang, Silvia S.

    2016-01-01

    The central nervous system (CNS) is a finely tuned organ that participates in nearly every aspect of our day-to-day function. Neurons lie at the core of this functional unit and maintain an active dialogue with one another as well as their fellow CNS residents (e.g. astrocytes, oligodendrocytes, microglia). Because of this complex dialogue, it is essential that the CNS milieu be tightly regulated in order to permit uninterrupted and efficient neural chemistry. This is accomplished in part by anatomical barriers that segregate vascular components from the cerebral spinal fluid (CSF) and brain parenchyma. These barriers impede entry of noxious materials and enable the CNS to maintain requisite protein and ionic balances for constant electrochemical signaling. Under homeostatic conditions, the CNS is protected by the presence of specialized endothelium/epithelium, the blood brain barrier (BBB), and the blood-CSF barrier. However, following CNS infection these protective barriers can be comprised, sometimes resulting in severe neurological complications triggered by an imbalance or blockage of neural chemistry. In some instances, these disruptions are severe enough to be fatal. This review focuses on a selection of microbes (both viruses and parasites) that compromise vascular barriers and induce neurological complications upon gaining access to the CNS. Emphasis is placed on CNS diseases that result from a pathogenic interplay between host immune defenses and the invading microbe. PMID:20401700

  18. Mechanisms of Hypothermia, Delayed Hyperthermia and Fever Following CNS Injury

    EPA Science Inventory

    Central nervous system (CNS) damage is often associated with robust body temperature changes, such as hypothermia and delayed hyperthermia. Hypothermia is one of the most common body temperature changes to CNS insults in rodents and is often associated with improved outcome. Alth...

  19. CNS Involvement in AML Patient Treated with 5-Azacytidine

    PubMed Central

    Vasilatou, Diamantina; Papageorgiou, Sotirios; Bazani, Efthymia; Prasouli, Athina; Economopoulou, Christina; Roumpakis, Christoforos; Karakitsos, Petros; Dimitriadis, George; Pappa, Vasiliki

    2014-01-01

    Central nervous system (CNS) involvement in acute myeloid leukemia (AML) is a rare complication of the disease and is associated with poor prognosis. Sometimes the clinical presentation can be unspecific and the diagnosis can be very challenging. Here we report a case of CNS infiltration in a patient suffering from AML who presented with normal complete blood count and altered mental status. PMID:25197583

  20. CNS Involvement in AML Patient Treated with 5-Azacytidine.

    PubMed

    Vasilatou, Diamantina; Papageorgiou, Sotirios; Bazani, Efthymia; Prasouli, Athina; Economopoulou, Christina; Roumpakis, Christoforos; Karakitsos, Petros; Dimitriadis, George; Pappa, Vasiliki

    2014-01-01

    Central nervous system (CNS) involvement in acute myeloid leukemia (AML) is a rare complication of the disease and is associated with poor prognosis. Sometimes the clinical presentation can be unspecific and the diagnosis can be very challenging. Here we report a case of CNS infiltration in a patient suffering from AML who presented with normal complete blood count and altered mental status. PMID:25197583

  1. The role of dendritic cells in CNS autoimmunity

    PubMed Central

    Zozulya, Alla L.; Clarkson, Benjamin D.; Ortler, Sonja; Fabry, Zsuzsanna

    2010-01-01

    Multiple sclerosis (MS) is a chronic immune-mediated, central nervous system (CNS) demyelinating disease. Clinical and histopathological features suggest an inflammatory etiology involving resident CNS innate cells as well as invading adaptive immune cells. Encephalitogenic myelin-reactive T cells have been implicated in the initiation of an inflammatory cascade, eventually resulting in demyelination and axonal damage (the histological hallmarks of MS). Dendritic cells (DC) have recently emerged as key modulators of this immunopathological cascade, as supported by studies in humans and experimental disease models. In one such model, experimental autoimmune encephalomyelitis (EAE), CNS microvessel-associated DC have been shown to be essential for local antigen recognition by myelin-reactive T cells. Moreover, the functional state and compartmental distribution of DC derived from CNS and associated lymphatics seem to be limiting factors in both the induction and effector phases of EAE. Moreover, DC modulate and balance the recruitment of encephalitogenic and regulatory T cells into CNS tissue. This capacity is critically influenced by DC surface expression of co-stimulatory or co-inhibitory molecules. The fact that DC accumulate in the CNS before T cells and can direct T-cell responses suggests that they are key determinants of CNS autoimmune outcomes. Here we provide a comprehensive review of recent advances in our understanding of CNS-derived DC and their relevance to neuroinflammation. PMID:20217033

  2. Camel Streptococcus agalactiae populations are associated with specific disease complexes and acquired the tetracycline resistance gene tetM via a Tn916-like element

    PubMed Central

    2013-01-01

    Camels are the most valuable livestock species in the Horn of Africa and play a pivotal role in the nutritional sustainability for millions of people. Their health status is therefore of utmost importance for the people living in this region. Streptococcus agalactiae, a Group B Streptococcus (GBS), is an important camel pathogen. Here we present the first epidemiological study based on genetic and phenotypic data from African camel derived GBS. Ninety-two GBS were characterized using multilocus sequence typing (MLST), capsular polysaccharide typing and in vitro antimicrobial susceptibility testing. We analysed the GBS using Bayesian linkage, phylogenetic and minimum spanning tree analyses and compared them with human GBS from East Africa in order to investigate the level of genetic exchange between GBS populations in the region. Camel GBS sequence types (STs) were distinct from other STs reported so far. We mapped specific STs and capsular types to major disease complexes caused by GBS. Widespread resistance (34%) to tetracycline was associated with acquisition of the tetM gene that is carried on a Tn916-like element, and observed primarily among GBS isolated from mastitis. The presence of tetM within different MLST clades suggests acquisition on multiple occasions. Wound infections and mastitis in camels associated with GBS are widespread and should ideally be treated with antimicrobials other than tetracycline in East Africa. PMID:24083845

  3. Cognitive Impairment and Persistent CNS Injury in Treated HIV.

    PubMed

    Chan, Phillip; Hellmuth, Joanna; Spudich, Serena; Valcour, Victor

    2016-08-01

    The implementation of combination antiretroviral therapy (cART) has changed HIV infection into a chronic illness, conveying extensive benefits, including greater longevity and advantages for the central nervous system (CNS). However, studies increasingly confirm that the CNS gains are incomplete, with reports of persistent immune activation affecting the CNS despite suppression of plasma HIV RNA. The rate of cognitive impairment is unchanged, although severity is generally milder than in the pre-cART era. In this review, we discuss cognitive outcomes from recently published clinical HIV studies, review observations on HIV biomarkers for cognitive change, and emphasize longitudinal imaging findings. Additionally, we summarize recent studies on CNS viral invasion, CD8 encephalitis, and how CNS involvement during the earliest stages of infection may set the stage for later cognitive manifestations. PMID:27188299

  4. PPAR Regulation of Inflammatory Signaling in CNS Diseases

    PubMed Central

    Bright, John J.; Kanakasabai, Saravanan; Chearwae, Wanida; Chakraborty, Sharmistha

    2008-01-01

    Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPARα, γ, and δ isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-κB and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases. PMID:18670616

  5. Community-acquired pneumonia.

    PubMed

    Falguera, M; Ramírez, M F

    2015-11-01

    This article not only reviews the essential aspects of community-acquired pneumonia for daily clinical practice, but also highlights the controversial issues and provides the newest available information. Community-acquired pneumonia is considered in a broad sense, without excluding certain variants that, in recent years, a number of authors have managed to delineate, such as healthcare-associated pneumonia. The latter form is nothing more than the same disease that affects more frail patients, with a greater number of risk factors, both sharing an overall common approach. PMID:26186969

  6. A Philosophy for CNS Radiotracer Design

    PubMed Central

    2015-01-01

    Conspectus Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods

  7. Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency.

    PubMed

    Moretti, Paolo; Peters, Sarika U; Del Gaudio, Daniela; Sahoo, Trilochan; Hyland, Keith; Bottiglieri, Teodoro; Hopkin, Robert J; Peach, Elizabeth; Min, Sang Hee; Goldman, David; Roa, Benjamin; Bacino, Carlos A; Scaglia, Fernando

    2008-07-01

    We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities. PMID:18027081

  8. Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency

    PubMed Central

    Moretti, Paolo; Peters, Sarika U.; del Gaudio, Daniela; Sahoo, Trilochan; Hyland, Keith; Bottiglieri, Teodoro; Hopkin, Robert J.; Peach, Elizabeth; Min, Sang Hee; Goldman, David; Roa, Benjamin

    2014-01-01

    We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities. PMID:18027081

  9. Acquired Brain Injury Program.

    ERIC Educational Resources Information Center

    Schwartz, Stacey Hunter

    This paper reviews the Acquired Brain Injury (ABI) Program at Coastline Community College (California). The ABI Program is a two-year, for-credit educational curriculum designed to provide structured cognitive retraining for adults who have sustained an ABI due to traumatic (such as motor vehicle accident or fall) or non-traumatic(such as…

  10. Acquired von Willebrand disease.

    PubMed

    Petrini, P

    1999-05-01

    Acquired von Willebrand disease (AvWD) is a syndrome that has clinical and laboratory features similar to hereditary vWD. In contrast to the latter it occurs in patients without a family history of previous bleeding tendency. PMID:23401904

  11. NFIA Haploinsufficiency Is Associated with a CNS Malformation Syndrome and Urinary Tract Defects

    PubMed Central

    Alkuraya, Fowzan S; Donovan, Diana J; Xi, Qiongchao; Turbe-Doan, Annick; Li, Qing-Gang; Campbell, Craig G; Shanske, Alan L; Sherr, Elliott H; Ahmad, Ayesha; Peters, Roxana; Rilliet, Benedict; Parvex, Paloma; Bassuk, Alexander G; Harris, David J; Ferguson, Heather; Kelly, Chantal; Walsh, Christopher A; Gronostajski, Richard M; Devriendt, Koenraad; Higgins, Anne; Ligon, Azra H; Quade, Bradley J; Morton, Cynthia C; Gusella, James F; Maas, Richard L

    2007-01-01

    Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia−/− knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia+/− and Nfia−/− phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia+/− and Nfia−/− mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects. PMID:17530927

  12. Amyloidosis, Synucleinopathy, and Prion Encephalopathy in a Neuropathic Lysosomal Storage Disease: The CNS-Biomarker Potential of Peripheral Blood

    PubMed Central

    Naughton, Bartholomew J.; Duncan, F. Jason; Murrey, Darren; Ware, Tierra; Meadows, Aaron; McCarty, Douglas M.; Fu, Haiyan

    2013-01-01

    Mucopolysaccharidosis (MPS) IIIB is a devastating neuropathic lysosomal storage disease with complex pathology. This study identifies molecular signatures in peripheral blood that may be relevant to MPS IIIB pathogenesis using a mouse model. Genome-wide gene expression microarrays on pooled RNAs showed dysregulation of 2,802 transcripts in blood from MPS IIIB mice, reflecting pathological complexity of MPS IIIB, encompassing virtually all previously reported and as yet unexplored disease aspects. Importantly, many of the dysregulated genes are reported to be tissue-specific. Further analyses of multiple genes linked to major pathways of neurodegeneration demonstrated a strong brain-blood correlation in amyloidosis and synucleinopathy in MPS IIIB. We also detected prion protein (Prnp) deposition in the CNS and Prnp dysregulation in the blood in MPS IIIB mice, suggesting the involvement of Prnp aggregation in neuropathology. Systemic delivery of trans-BBB-neurotropic rAAV9-hNAGLU vector mediated not only efficient restoration of functional α-N-acetylglucosaminidase and clearance of lysosomal storage pathology in the central nervous system (CNS) and periphery, but also the correction of impaired neurodegenerative molecular pathways in the brain and blood. Our data suggest that molecular changes in blood may reflect pathological status in the CNS and provide a useful tool for identifying potential CNS-specific biomarkers for MPS IIIB and possibly other neurological diseases. PMID:24278249

  13. Therapeutic challenges in primary CNS lymphoma.

    PubMed

    Morris, Patrick G; Abrey, Lauren E

    2009-06-01

    Optimum treatment for patients with primary CNS lymphoma remains challenging because there have not been any large randomised clinical trials of this rare tumour. Drugs used in treating systemic non-Hodgkin lymphoma have mostly proven ineffective because of difficulties crossing the blood-brain barrier. The recognition of the efficacy of high-dose methotrexate was a substantial therapeutic breakthrough and further advances, such as the development of polychemotherapy regimens, have built on this. Whole-brain radiotherapy can consolidate response to chemotherapy, but the associated toxic effects of chemoradiation can be unacceptable. Other effective approaches include disruption of the blood-brain barrier and the use of high-dose chemotherapy. Recently, there have been attempts to optimise multi-drug chemotherapy regimens by focusing on improving survival and reducing toxic effects. A promising area of research is the incorporation of novel targeted drugs into standard treatment frameworks. In the future, greater cooperation between research groups should hopefully lead to further therapeutic advances. PMID:19446277

  14. Sentinel lesions of primary CNS lymphoma.

    PubMed Central

    Alderson, L; Fetell, M R; Sisti, M; Hochberg, F; Cohen, M; Louis, D N

    1996-01-01

    Some patients ultimately diagnosed with primary CNS lymphoma (PCNSL) have transient symptomatic contrast enhancing lesions. These "sentinel lesions" of PCNSL recede spontaneously or with corticosteroid treatment and present an important diagnostic dilemma because they show variable, but non-diagnostic histopathological features. Four previously healthy, immunocompetent patients aged 49 to 58 years had contrast enhancing intraparenchymal brain lesions. Before biopsy, three of the four were treated with corticosteroids. Initial biopsies showed demyelination with axonal sparing in two, non-specific inflammation in one, and normal brain in one. Infiltrating lymphocytes predominantly expressed T cell markers with rare B cells. All four patients recovered within two to four weeks after the initial biopsy and imaging studies showed resolution of the lesions. The CSF was normal in three of the four patients tested; oligoclonal bands were absent in both of the two tested. After seven to 11 months, each patient developed new symptomatic lesions in a different region of the brain, biopsy of which showed a B cell PCNSL. The mechanism of spontaneous involution of sentinel lesions is not understood, but may represent host immunity against the tumour. Sentinel lesions of PCNSL should be considered in patients with contrast enhancing focal parenchymal lesions that show non-specific or demyelinative histopathological changes. Close clinical and radiographic follow up is essential if PCNSL is to be diagnosed early in such patients. Images PMID:8558135

  15. Clinical Potential of Neurosteroids for CNS Disorders.

    PubMed

    Reddy, Doodipala Samba; Estes, William A

    2016-07-01

    Neurosteroids are key endogenous molecules in the brain that affect many neural functions. We describe here recent advances in US National Institutes of Health (NIH)-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neurosteroids can maximally enhance synaptic phasic and extrasynaptic tonic inhibition. The resulting chloride current conductance generates a form of shunting inhibition that controls network excitability, seizures, and behavior. Such mechanisms of neurosteroids are providing innovative therapies for epilepsy, status epilepticus (SE), traumatic brain injury (TBI), fragile X syndrome (FXS), and chemical neurotoxicity. The neurosteroid field has entered a new era, and many compounds have reached advanced clinical trials. Synthetic analogs have several advantages over natural neurosteroids for clinical use because of their superior bioavailability and safety trends. PMID:27156439

  16. Cell encapsulation technology as a therapeutic strategy for CNS malignancies.

    PubMed Central

    Visted, T.; Bjerkvig, R.; Enger, P. O.

    2001-01-01

    Gene therapy using viral vectors has to date failed to reveal its definitive clinical usefulness. Cell encapsulation technology represents an alternative, nonviral approach for the delivery of biologically active compounds to tumors. This strategy involves the use of genetically engineered producer cells that secrete a protein with therapeutic potential. The cells are encapsulated in an immunoisolating material that makes them suitable for transplantation. The capsules, or bioreactors, permit the release of recombinant proteins that may assert their effects in the tumor microenvironment. During the last decades, there has been significant progress in the development of encapsulation technologies that comprise devices for both macro- and microencapsulation. The polysaccharide alginate is the most commonly used material for cell encapsulation and is well tolerated by various tissues. A wide spectrum of cells and tissues has been encapsulated and implanted, both in animals and humans, indicating the general applicability of this approach for both research and medical purposes, including CNS malignancies. Gliomas most frequently recur at the resection site. To provide local and sustained drug delivery, the bioreactors can be implanted in the brain parenchyma or in the ventricular system. The development of comprehensive analyses of geno- and phenotypic profiles of a tumor (genomics and proteomics) may provide new and important guidelines for choosing the optimal combination of bioreactors and recombinant proteins for therapeutic use. PMID:11465401

  17. CNS GLP-1 Regulation of Peripheral Glucose Homeostasis

    PubMed Central

    Sandoval, Darleen

    2008-01-01

    Current models hold that peripheral and CNS GLP-1 signaling operate as distinct systems whereby CNS GLP-1 regulates food intake and circulating GLP-1 regulates glucose homeostasis. There is accumulating evidence that the arcuate nucleus, an area of the CNS that regulates energy homeostasis, responds to hormones and nutrients to regulate glucose homeostasis as well. Recent data suggest that GLP-1 may be another signal acting on the arcuate to regulate glucose homeostasis challenging the conventional model of GLP-1 physiology. This review discusses the peripheral and central GLP-1 systems and presents a model whereby these systems are integrated in regulation of glucose homeostasis. PMID:18508100

  18. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair

    PubMed Central

    London, Anat; Cohen, Merav; Schwartz, Michal

    2013-01-01

    Functional macrophage heterogeneity is recognized outside the central nervous system (CNS), where alternatively activated macrophages can perform immune-resolving functions. Such functional heterogeneity was largely ignored in the CNS, with respect to the resident microglia and the myeloid-derived cells recruited from the blood following injury or disease, previously defined as blood-derived microglia; both were indistinguishably perceived detrimental. Our studies have led us to view the myeloid-derived infiltrating cells as functionally distinct from the resident microglia, and accordingly, to name them monocyte-derived macrophages (mo-MΦ). Although microglia perform various maintenance and protective roles, under certain conditions when they can no longer provide protection, mo-MΦ are recruited to the damaged CNS; there, they act not as microglial replacements but rather assistant cells, providing activities that cannot be timely performed by the resident cells. Here, we focus on the functional heterogeneity of microglia/mo-MΦ, emphasizing that, as opposed to the mo-MΦ, microglia often fail to timely acquire the phenotype essential for CNS repair. PMID:23596391

  19. Acquired von Willebrand disease.

    PubMed

    Kumar, Shaji; Pruthi, Rajiv K; Nichols, William L

    2002-02-01

    Acquired von Willebrand disease (AvWD) is a relatively rare acquired bleeding disorder that usually occurs in elderly patients, in whom its recognition may be delayed. Patients usually present predominantly with mucocutaneous bleeding, with no previous history of bleeding abnormalities and no clinically meaningful family history. Various underlying diseases have been associated with AvWD, most commonly hematoproliferative disorders, including monoclonal gammopathies, lymphoproliferative disorders, and myeloproliferative disorders. The pathogenesis of AvWD remains incompletely understood but includes autoantibodies directed against the von Willebrand factor (vWF), leading to a more rapid clearance from the circulation or interference with its function, adsorption of vWF by tumor cells, and nonimmunologic mechanisms of destruction. Laboratory evaluation usually reveals a pattern of prolonged bleeding time and decreased levels of vWF antigen, ristocetin cofactor activity, and factor VIII coagulant activity consistent with a diagnosis of vWD. Acquired vWD is distinguished from the congenital form by age at presentation, absence of a personal and family history of bleeding disorders, and, often, presence of a hematoproliferative or autoimmune disorder. The severity of the bleeding varies considerably among patients. Therapeutic options include desmopressin and certain factor VIII concentrates that also contain vWF. Successful treatment of the associated illness can reverse the clinical and laboratory manifestations. Intravenous immunoglobulins have also shown some efficacy in the management of AvWD, especially cases associated with monoclonal gammopathies. Awareness of AvWD is essential for diagnosis and appropriate management. PMID:11838652

  20. Early CNS neurodegeneration in radiologically isolated syndrome

    PubMed Central

    Overton, Eve; Khadka, Sankalpa; Buckley, Jessica; Liu, Shuang; Sampat, Mehul; Kantarci, Orhun; Lebrun Frenay, Christine; Siva, Aksel; Okuda, Darin T.; Pelletier, Daniel

    2015-01-01

    Objective: Increasing evidence indicates that the thalamus may be a location of early neurodegeneration in multiple sclerosis (MS). Our objective was to identify the presence of gray matter volume loss and thinning in patients with radiologically isolated syndrome (RIS). Methods: Sixty-three participants were included in this case-control study. Twenty-one patients with RIS were age- and sex-matched to 42 healthy controls in a 1:2 ratio. All participants underwent brain MRIs on a single 3T scanner. After lesion segmentation and inpainting, 1 mm3-isometric T1-weighted images were submitted to FreeSurfer (v5.2). Normalized cortical and deep gray matter volumes were compared between patients with RIS and controls using t tests, and thalamic volumes were correlated with white matter lesion volumes using Pearson correlation. Exploratory cortical thickness maps were created. Results: Although traditional normalized total gray and white matter volumes were not statistically different between patients with RIS and controls, normalized left (0.0046 ± 0.0005 vs 0.0049 ± 0.0004, p = 0.006), right (0.0045 ± 0.0005 vs 0.0048 ± 0.0004, p = 0.008), and mean (0.0045 ± 0.0005 vs 0.0049 ± 0.0004, p = 0.004) thalamic volumes were significantly lower in patients with RIS (n = 21, mean age 41.9 ± 12.7 years) than in controls (n = 42, mean age 41.4 ± 11.2 years). Thalamic volumes correlated modestly with white matter lesion volumes (range: r = −0.35 to −0.47). Conclusion: Our data provide novel evidence of thalamic atrophy in RIS and are consistent with previous reports in early MS stages. Thalamic volume loss is present early in CNS demyelinating disease and should be further investigated as a metric associated with neurodegeneration. PMID:25884012

  1. The Processing of Airspace Concept Evaluations Using FASTE-CNS as a Pre- or Post-Simulation CNS Analysis Tool

    NASA Technical Reports Server (NTRS)

    Mainger, Steve

    2004-01-01

    As NASA speculates on and explores the future of aviation, the technological and physical aspects of our environment increasing become hurdles that must be overcome for success. Research into methods for overcoming some of these selected hurdles have been purposed by several NASA research partners as concepts. The task of establishing a common evaluation environment was placed on NASA's Virtual Airspace Simulation Technologies (VAST) project (sub-project of VAMS), and they responded with the development of the Airspace Concept Evaluation System (ACES). As one examines the ACES environment from a communication, navigation or surveillance (CNS) perspective, the simulation parameters are built with assumed perfection in the transactions associated with CNS. To truly evaluate these concepts in a realistic sense, the contributions/effects of CNS must be part of the ACES. NASA Glenn Research Center (GRC) has supported the Virtual Airspace Modeling and Simulation (VAMS) project through the continued development of CNS models and analysis capabilities which supports the ACES environment. NASA GRC initiated the development a communications traffic loading analysis tool, called the Future Aeronautical Sub-network Traffic Emulator for Communications, Navigation and Surveillance (FASTE-CNS), as part of this support. This tool allows for forecasting of communications load with the understanding that, there is no single, common source for loading models used to evaluate the existing and planned communications channels; and that, consensus and accuracy in the traffic load models is a very important input to the decisions being made on the acceptability of communication techniques used to fulfill the aeronautical requirements. Leveraging off the existing capabilities of the FASTE-CNS tool, GRC has called for FASTE-CNS to have the functionality to pre- and post-process the simulation runs of ACES to report on instances when traffic density, frequency congestion or aircraft spacing

  2. Community-Acquired urinary tract infection by pseudomonas oryzihabitans

    PubMed Central

    Bhatawadekar, Sunita M

    2013-01-01

    Pseudomonas oryzihabitans and Chrysomonas luteola has been placed in CDC group Ve2 and Ve1 respectively. These bacteria appear to be emerging pathogens. P. oryzihabitans was isolated from cases of bacteremia, CNS infections, wound infections, peritonitis, sinusitis, catheter associated infections in AIDS patient, and pneumonia. Most of the reports of P. oryzihabitans infection were of nosocomial origin in individuals with some predisposing factors. We report here a case of community acquired UTI by P. oryzihabitans in an immune-competent patient with stricture of urethra. PMID:23853437

  3. Community-Acquired urinary tract infection by pseudomonas oryzihabitans.

    PubMed

    Bhatawadekar, Sunita M

    2013-04-01

    Pseudomonas oryzihabitans and Chrysomonas luteola has been placed in CDC group Ve2 and Ve1 respectively. These bacteria appear to be emerging pathogens. P. oryzihabitans was isolated from cases of bacteremia, CNS infections, wound infections, peritonitis, sinusitis, catheter associated infections in AIDS patient, and pneumonia. Most of the reports of P. oryzihabitans infection were of nosocomial origin in individuals with some predisposing factors. We report here a case of community acquired UTI by P. oryzihabitans in an immune-competent patient with stricture of urethra. PMID:23853437

  4. Receptor Tyrosine Kinases: Molecular Switches Regulating CNS Axon Regeneration

    PubMed Central

    Vigneswara, Vasanthy; Kundi, Sarina; Ahmed, Zubair

    2012-01-01

    The poor or lack of injured adult central nervous system (CNS) axon regeneration results in devastating consequences and poor functional recovery. The interplay between the intrinsic and extrinsic factors contributes to robust inhibition of axon regeneration of injured CNS neurons. The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury. In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands. This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration. PMID:22848811

  5. Pushing Forward: Remyelination as the New Frontier in CNS Diseases.

    PubMed

    Kremer, David; Göttle, Peter; Hartung, Hans-Peter; Küry, Patrick

    2016-04-01

    The evolutionary acquisition of myelin sheaths around large caliber axons in the central nervous system (CNS) represented a milestone in the development of vertebrate higher brain function. Myelin ensheathment of axons enabled saltatory conduction and thus accelerated information processing. However, a number of CNS diseases harm or destroy myelin and oligodendrocytes (myelin-producing cells), ultimately resulting in demyelination. In the adult CNS, new oligodendrocytes can be generated from a quiescent pool of precursor cells, which - upon differentiation - can replace lost myelin sheaths. The efficiency of this spontaneous regeneration is limited, which leads to incomplete remyelination and residual clinical symptoms. Here, we discuss CNS pathologies characterized by white matter degeneration and regeneration and highlight drugs that could potentially serve as remyelination therapies. PMID:26964504

  6. Human African trypanosomiasis of the CNS: current issues and challenges

    PubMed Central

    Kennedy, Peter G.E.

    2004-01-01

    Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. Current therapy with melarsoprol for CNS HAT has unacceptable side-effects with an overall mortality of 5%. This review discusses the issues of diagnosis and staging of CNS disease, its neuropathogenesis, and the possibility of new therapies for treating late-stage disease. PMID:14966556

  7. The role of the NG2 proteoglycan in OPC and CNS network function.

    PubMed

    Sakry, Dominik; Trotter, Jacqueline

    2016-05-01

    In the normal mammalian CNS, the NG2 proteoglycan is expressed by oligodendrocyte precursor cells (OPC) but not by any other neural cell-type. NG2 is a type-1 membrane protein, exerting multiple roles in the CNS including intracellular signaling within the OPC, with effects on migration, cytoskeleton interaction and target gene regulation. It has been recently shown that the extracellular region of NG2, in addition to an adhesive function, acts as a soluble ECM component with the capacity to alter defined neuronal network properties. This region of NG2 is thus endowed with neuromodulatory properties. In order to generate biologically active fragments yielding these properties, the sequential cleavage of the NG2 protein by α- and γ-secretases occurs. The basal level of constitutive cleavage is stimulated by neuronal network activity. This processing leads to 4 major NG2 fragments which all have been associated with distinct biological functions. Here we summarize these functions, focusing on recent discoveries and their implications for the CNS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only). PMID:26100334

  8. Presence of the Panton-Valentine Leukocidin Genes in Methicillin-Resistant Staphylococcus aureus Is Associated with Severity and Clinical Outcome of Hospital-Acquired Pneumonia in a Single Center Study in China

    PubMed Central

    Zhang, Chuanling; Guo, Liang; Chu, Xu; Shen, Limeng; Guo, Yuanyu; Dong, Huali; Mao, Jianfeng; van der Veen, Stijn

    2016-01-01

    The Panton-Valentine leukocidin (PVL) genes of methicillin-resistant Staphylococcus aureus (MRSA) have previously been associated with severe infections. Here, the impact of the PVL genes on severity of disease and clinical outcome of patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) due to MRSA was investigated in a single center observational study in a hospital in China. HAP due to MRSA was diagnosed in 100 patients and 13 of the patients were PVL positive, while VAP was diagnosed in 5 patients and 2 were PVL positive. The PVL positive patient group showed a significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (14.3 ±7.8 vs. 10.1 ±4.7, P = 0.005) and significantly more patients with CRP levels >80 mg/L (8/15 vs. 12/90, P = 0.006) or WBC counts >15x109/L (7/15 vs. 12/90, P = 0.006), indicating that the severity of disease is affected by the presence of the PVL genes. The outcome of the study was defined by 30-day mortality. Four (27%) of the PVL positive patients and four (4%) of the PVL negative patients died within 30 days (P = 0.01, Fisher exact test). Kaplan-Meier survival curves were generated for the PVL positive and PVL negative patient groups, which differed significantly (P = 0.003). Among the patients that died, the mean interval between diagnosis and death was shorter for the PVL positive patients (9.3 ±5.6 vs. 40.8 ±6.6 days, P = 0.013). Further analysis within the HAP and VAP patient groups showed that the presence of PVL in MRSA impacted the severity of disease and clinical outcome of HAP, but for VAP the number of patients included in the study was too low. In conclusion, in this single center study in a Chinese hospital the presence of the PVL genes in MRSA impacted the severity of disease and clinical outcome in patients with HAP due to MRSA. PMID:27249225

  9. Presence of the Panton-Valentine Leukocidin Genes in Methicillin-Resistant Staphylococcus aureus Is Associated with Severity and Clinical Outcome of Hospital-Acquired Pneumonia in a Single Center Study in China.

    PubMed

    Zhang, Chuanling; Guo, Liang; Chu, Xu; Shen, Limeng; Guo, Yuanyu; Dong, Huali; Mao, Jianfeng; van der Veen, Stijn

    2016-01-01

    The Panton-Valentine leukocidin (PVL) genes of methicillin-resistant Staphylococcus aureus (MRSA) have previously been associated with severe infections. Here, the impact of the PVL genes on severity of disease and clinical outcome of patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) due to MRSA was investigated in a single center observational study in a hospital in China. HAP due to MRSA was diagnosed in 100 patients and 13 of the patients were PVL positive, while VAP was diagnosed in 5 patients and 2 were PVL positive. The PVL positive patient group showed a significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (14.3 ±7.8 vs. 10.1 ±4.7, P = 0.005) and significantly more patients with CRP levels >80 mg/L (8/15 vs. 12/90, P = 0.006) or WBC counts >15x109/L (7/15 vs. 12/90, P = 0.006), indicating that the severity of disease is affected by the presence of the PVL genes. The outcome of the study was defined by 30-day mortality. Four (27%) of the PVL positive patients and four (4%) of the PVL negative patients died within 30 days (P = 0.01, Fisher exact test). Kaplan-Meier survival curves were generated for the PVL positive and PVL negative patient groups, which differed significantly (P = 0.003). Among the patients that died, the mean interval between diagnosis and death was shorter for the PVL positive patients (9.3 ±5.6 vs. 40.8 ±6.6 days, P = 0.013). Further analysis within the HAP and VAP patient groups showed that the presence of PVL in MRSA impacted the severity of disease and clinical outcome of HAP, but for VAP the number of patients included in the study was too low. In conclusion, in this single center study in a Chinese hospital the presence of the PVL genes in MRSA impacted the severity of disease and clinical outcome in patients with HAP due to MRSA. PMID:27249225

  10. Insights into the physiological role of CNS regeneration inhibitors

    PubMed Central

    Baldwin, Katherine T.; Giger, Roman J.

    2015-01-01

    The growth inhibitory nature of injured adult mammalian central nervous system (CNS) tissue constitutes a major barrier to robust axonal outgrowth and functional recovery following trauma or disease. Prototypic CNS regeneration inhibitors are broadly expressed in the healthy and injured brain and spinal cord and include myelin-associated glycoprotein (MAG), the reticulon family member NogoA, oligodendrocyte myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans (CSPGs). These structurally diverse molecules strongly inhibit neurite outgrowth in vitro, and have been most extensively studied in the context of nervous system injury in vivo. The physiological role of CNS regeneration inhibitors in the naïve, or uninjured, CNS remains less well understood, but has received growing attention in recent years and is the focus of this review. CNS regeneration inhibitors regulate myelin development and axon stability, consolidate neuronal structure shaped by experience, and limit activity-dependent modification of synaptic strength. Altered function of CNS regeneration inhibitors is associated with neuropsychiatric disorders, suggesting crucial roles in brain development and health. PMID:26113809

  11. CNS-related side-effects with metoprolol and atenolol.

    PubMed

    Cove-Smith, J R; Kirk, C A

    1985-01-01

    Vivid and bizarre dreams, hallucinations, sleep disturbance and psychosis have all been described following treatment with beta-blockers. It has been suggested that these central nervous system (CNS) side-effects are related to the degree of lipophilicity of the beta-blocker. A randomized double-blind crossover study was performed to compare the incidence of CNS side-effects with atenolol and metoprolol in hypertensive patients who had reported CNS side-effects with lipophilic beta-blockers. Eleven women and six men completed the study, in which a 30-item psychiatric questionnaire was used to detect changes in psychological status and possible CNS side-effects. Discontinuation of the original lipophilic beta-blocker produced a significant improvement in quality of sleep, dreams, concentration, memory, energy, and anxiety. No significant CNS side-effects were reported with atenolol, but introduction of metoprolol caused a significant increase in the incidence of sleep disturbance (p less than 0.01) and restless nights (p less than 0.05), as well as failure to achieve satisfactory sexual intercourse (p less than 0.05). When compared with atenolol, metoprolol was associated with a significantly higher incidence of restless disturbed nights (p less than 0.05). Blood pressure control was identical for both beta-blockers. This study appears to confirm the association between CNS-related side-effects and the lipophilicity of beta-blockers. PMID:4054193

  12. Recombinant adeno-associated virus vector: use for transgene expression and anterograde tract tracing in the CNS

    PubMed Central

    Chamberlin, Nancy L.; Du, Bin; de Lacalle, Sonsoles; Saper, Clifford B.

    2016-01-01

    We used a recombinant adeno-associated virus vector (AAV) to deliver a foreign gene, green fluorescent protein (GFP), into mature neurons in adult rat CNS in vivo. Microinjections of AAV as small as 50 nl transduced hundreds of neurons at the injection site. There was virtually no retrograde transport as fewer than one neuron per brain was found distant from the injection site that exhibited GFP immunoreactivity. The gene product, GFP, filled the entire neuronal cytoplasmic compartment; GFP immunoreactivity was robust in cell bodies, axons, and nerve terminals. There was no tissue damage at the injection sites or pathogenicity indicated by changes in astrocytic or microglial markers. There was no inflammatory response as judged by leukocytic invasion. Gene expression in transduced cells was robust and apparently permanent: there was no evidence of phenotypic reversion up to 12 weeks following infection. AAV is an excellent vector for introducing foreign genes into mature CNS neurons. Not only might it be an ideal vehicle for gene therapy, but also the GFP-containing AAV presents a new strategy for tracing long axonal pathways in the CNS, which is difficult with current tracers (PHAL, biotinylated dextrans). PMID:9630611

  13. [Acquired von Willebrand syndrome].

    PubMed

    Franchini, Massimo

    2006-01-01

    Acquired von Willebrand syndrome (aVWS) is a rare, but probably underestimated, bleeding disorder that mimics the congenital form of von Willebrand disease (VWD) in terms of laboratory findings and clinical presentation. However, unlike congenital VWD, it arises in individuals with no personal or family history of bleeding. AVWS occurs in association with a variety of underlying disorders, including lymphoproliferative disorders, myeloproliferative disorders and cardiovascular diseases. The main pathogenic, clinical, laboratory and therapeutic aspects of this syndrome are concisely reported in this review. PMID:16913181

  14. Widespread gene transfer in the central nervous system of cynomolgus macaques following delivery of AAV9 into the cisterna magna.

    PubMed

    Hinderer, Christian; Bell, Peter; Vite, Charles H; Louboutin, Jean-Pierre; Grant, Rebecca; Bote, Erin; Yu, Hongwei; Pukenas, Bryan; Hurst, Robert; Wilson, James M

    2014-01-01

    Adeno-associated virus serotype 9 (AAV9) vectors have recently been shown to transduce cells throughout the central nervous system of nonhuman primates when injected into the cerebrospinal fluid (CSF), a finding which could lead to a minimally invasive approach to treat genetic and acquired diseases affecting the entire CNS. We characterized the transduction efficiency of two routes of vector administration into the CSF of cynomolgus macaques-lumbar puncture, which is typically used in clinical practice, and suboccipital puncture, which is more commonly used in veterinary medicine. We found that delivery of vector into the cisterna magna via suboccipital puncture is up to 100-fold more efficient for achieving gene transfer to the brain. In addition, we evaluated the inflammatory response to AAV9-mediated GFP expression in the nonhuman primate CNS. We found that while CSF lymphocyte counts increased following gene transfer, there were no clinical or histological signs of immune toxicity. Together these data indicate that delivery of AAV9 into the cisterna magna is an effective method for achieving gene transfer in the CNS, and suggest that adapting this uncommon injection method for human trials could vastly increase the efficiency of gene delivery. PMID:26052519

  15. MyD88 expression by CNS-resident cells is pivotal for eliciting protective immunity in brain abscesses

    PubMed Central

    Garg, Sarita; Nichols, Jessica R; Esen, Nilufer; Liu, Shuliang; Phulwani, Nirmal K; Syed, Mohsin Md.; Wood, William H; Zhang, Yongqing; Becker, Kevin G; Aldrich, Amy; Kielian, Tammy

    2009-01-01

    MyD88 KO (knockout) mice are exquisitely sensitive to CNS (central nervous system) infection with Staphylococcus aureus, a common aetiological agent of brain abscess, exhibiting global defects in innate immunity and exacerbated tissue damage. However, since brain abscesses are typified by the involvement of both activated CNS-resident and infiltrating immune cells, in our previous studies it has been impossible to determine the relative contribution of MyD88-dependent signalling in the CNS compared with the peripheral immune cell compartments. In the present study we addressed this by examining the course of S. aureus infection in MyD88 bone marrow chimaera mice. Interestingly, chimaeras where MyD88 was present in the CNS, but not bone marrow-derived cells, mounted pro-inflammatory mediator expression profiles and neutrophil recruitment equivalent to or exceeding that detected in WT (wild-type) mice. These results implicate CNS MyD88 as essential in eliciting the initial wave of inflammation during the acute response to parenchymal infection. Microarray analysis of infected MyD88 KO compared with WT mice revealed a preponderance of differentially regulated genes involved in apoptotic pathways, suggesting that the extensive tissue damage characteristic of brain abscesses from MyD88 KO mice could result from dysregulated apoptosis. Collectively, the findings of the present study highlight a novel mechanism for CNS-resident cells in initiating a protective innate immune response in the infected brain and, in the absence of MyD88 in this compartment, immunity is compromised. PMID:19570030

  16. Airspace Concept Evaluation System (ACES), Concept Simulations using Communication, Navigation and Surveillance (CNS) System Models

    NASA Technical Reports Server (NTRS)

    Kubat, Greg; Vandrei, Don

    2006-01-01

    Project Objectives include: a) CNS Model Development; b Design/Integration of baseline set of CNS Models into ACES; c) Implement Enhanced Simulation Capabilities in ACES; d) Design and Integration of Enhanced (2nd set) CNS Models; and e) Continue with CNS Model Integration/Concept evaluations.

  17. More Than Cholesterol Transporters: Lipoprotein Receptors in CNS Function and Neurodegeneration

    PubMed Central

    Lane-Donovan, Courtney E.; Philips, Gary T.; Herz, Joachim

    2014-01-01

    Members of the low-density lipoprotein (LDL) receptor gene family have a diverse set of biological functions that transcend lipid metabolism. Lipoprotein receptors have broad effects in both the developing and adult brain and participate in synapse development, cargo trafficking, and signal transduction. In addition, several family members play key roles in Alzheimer's disease pathogenesis and neurodegeneration. This review summarizes our current understanding of the role lipoprotein receptors play in CNS function and AD pathology, with a special emphasis on amyloid-independent roles in endocytosis and synaptic dysfunction. PMID:25144875

  18. CNS accumulation of regulatory B cells is VLA-4-dependent

    PubMed Central

    Lehmann-Horn, Klaus; Sagan, Sharon A.; Winger, Ryan C.; Spencer, Collin M.; Bernard, Claude C.A.; Sobel, Raymond A.

    2016-01-01

    Objective: To investigate the role of very late antigen-4 (VLA-4) on regulatory B cells (Breg) in CNS autoimmune disease. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in mice selectively deficient for VLA-4 on B cells (CD19cre/α4f/f) by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (p)35–55 or recombinant human (rh) MOG protein. B-cell and T-cell populations were examined by flow cytometry and immunohistochemistry. Breg were evaluated by intracellular IL-10 staining of B cells and, secondly, by coexpression of CD1d and CD5. Results: As previously reported, EAE was less severe in B-cell VLA-4-deficient vs control CD19cre mice when induced by rhMOG, a model that is B-cell-dependent and leads to efficient B-cell activation and antibody production. Paradoxically, B-cell VLA-4-deficient mice developed more severe clinical disease than control mice when EAE was induced with MOG p35-55, a B-cell-independent encephalitogen that does not efficiently activate B cells. Peripheral T-cell and humoral immune responses were not altered in B-cell VLA-4-deficient mice. In MOG p35-55-induced EAE, B-cell VLA-4 deficiency reduced CNS accumulation of B but not T cells. Breg were detected in the CNS of control mice with MOG p35-55-induced EAE. However, more severe EAE in B-cell VLA-4-deficient mice was associated with virtual absence of CNS Breg. Conclusions: Our results demonstrate that CNS accumulation of Breg is VLA-4-dependent and suggest that Breg may contribute to regulation of CNS autoimmunity in situ. These observations underscore the need to choose the appropriate encephalitogen when studying how B cells contribute to pathogenesis or regulation of CNS autoimmunity. PMID:27027096

  19. Triptans and CNS side-effects: pharmacokinetic and metabolic mechanisms.

    PubMed

    Dodick, D W; Martin, V

    2004-06-01

    Triptans are the treatment of choice for acute migraine. While seemingly a homogenous group of drugs, results from a meta-analysis reveal significant differences in efficacy and tolerability among oral triptans. The incidence of drug-related central nervous system (CNS) side-effects with some triptans is as high as 15% and may be associated with functional impairment and reduced productivity. The occurrence of adverse events associated with triptans in general, and CNS side-effects in particular, may lead to a delay in initiating or even avoidance of an otherwise effective treatment. Potential explanations for differences among triptans in the incidence of CNS side-effects may relate to pharmacological and pharmacokinetic differences, including receptor binding, lipophilicity, and the presence of active metabolites. Of the triptans reviewed, at clinically relevant doses, almotriptan 12.5 mg, naratriptan 2.5 mg and sumatriptan 50 mg had the lowest incidence of CNS side-effects, while eletriptan 40 and 80 mg, rizatriptan 10 mg and zolmitriptan 2.5 and 5 mg had the highest incidence. The most likely explanations for the differences in CNS side-effects among triptans are the presence of active metabolites and high lipophilicity of the parent compound and active metabolites. Eletriptan, rizatriptan and zolmitriptan have active metabolites, while lipophilicity is lowest for almotriptan and sumatriptan. If CNS side-effects are a clinically relevant concern in the individual patient, use of a triptan with a low incidence of CNS side-effects may offer the potential for earlier initiation of treatment and more effective outcomes. PMID:15154851

  20. Actuarial risk of isolated CNS involvement in Ewing's sarcoma following prophylactic cranial irradiation and intrathecal methotrexate

    SciTech Connect

    Trigg, M.E.; Makuch, R.; Glaubiger, D.

    1985-04-01

    Records of 154 patients with Ewing's sarcoma treated at the National Cancer Institute were reviewed to assess the incidence and risk of developing isolated central nervous system (CNS) Ewing's sarcoma. Sixty-two of the 154 patients had received CNS irradiation and intrathecal (i.t.) methotrexate as part of their initial therapy to prevent the occurrence of isolated CNS Ewing's sarcoma. The risk of developing isolate CNS Ewing's sarcoma was greatest within the first two years after diagnosis and was approximately 10%. The overall risk of CNS recurrence in the group of patients receiving DNS treatment was similar to the group receiving no therapy directed to the CNS. The occurrence of isolated CNS involvement was not prevented by the use of CNS irradiation and i.t. methotrexate. Because of a lack of efficacy to the CNS irradiation regimen, current treatment regimens do not include therapy directed to CNS.

  1. AIDS: acquired immunodeficiency syndrome *

    PubMed Central

    Gilmore, N.J.; Beaulieu, R.; Steben, M.; Laverdière, M.

    1992-01-01

    Acquired immunodeficiency syndrome, or AIDS, is a new illness that occurs in previously healthy individuals. It is characterized by immunodeficiency, opportunistic infections and unusual malignant diseases. Life-threatening single or multiple infections with viruses, mycobacteria, fungi or protozoa are common. A rare neoplasm, Kaposi's sarcoma, has developed in approximately one third of patients with AIDS. More than 800 cases of AIDS have been reported in North America, over 24 of them in Canada. The majority of patients are male homosexuals, although AIDS has also developed in abusers of intravenously administered drugs, Haitian immigrants, individuals with hemophilia, recipients of blood transfusions, prostitutes, and infants, spouses and partners of patients with AIDS. The cause of AIDS is unknown, but the features are consistent with an infectious process. Early diagnosis can be difficult owing to the nonspecific symptoms and signs of the infections and malignant diseases. Therefore, vigilance by physicians is of the utmost importance. PMID:1544049

  2. Community-acquired pneumonia.

    PubMed

    Polverino, E; Torres Marti, A

    2011-02-01

    Despite the remarkable advances in antibiotic therapies, diagnostic tools, prevention campaigns and intensive care, community-acquired pneumonia (CAP) is still among the primary causes of death worldwide, and there have been no significant changes in mortality in the last decades. The clinical and economic burden of CAP makes it a major public health problem, particularly for children and the elderly. This issue provides a clinical overview of CAP, focusing on epidemiology, economic burden, diagnosis, risk stratification, treatment, clinical management, and prevention. Particular attention is given to some aspects related to the clinical management of CAP, such as the microbial etiology and the available tools to achieve it, the usefulness of new and old biomarkers, and antimicrobial and other non-antibiotic adjunctive therapies. Possible scenarios in which pneumonia does not respond to treatment are also analyzed to improve clinical outcomes of CAP. PMID:21242952

  3. Acquired Porphyria Cutanea Tarda

    PubMed Central

    Koval, Andrew; Danby, C. W. E.; Petermann, H.

    1965-01-01

    Currently, the porphyrias are classified in four main groups: congenital porphyria, acute intermittent porphyria, porphyria cutanea tarda hereditaria, and porphyria cutanea tarda symptomatica. The acquired form of porphyria (porphyria cutanea tarda symptomatica) occurs in older males and is nearly always associated with chronic alcoholism and hepatic cirrhosis. The main clinical changes are dermatological, with excessive skin fragility and photosensitivity resulting in erosions and bullae. Biochemically, high levels of uroporphyrin are found in the urine and stools. Treatment to date has been symptomatic and usually unsuccessful. A case of porphyria cutanea tarda symptomatica is presented showing dramatic improvement of both the skin lesions and porphyrin levels in urine and blood following repeated phlebotomy. Possible mechanisms of action of phlebotomy on porphyria cutanea tarda symptomatica are discussed. ImagesFig. 1Fig. 2 PMID:14341652

  4. [ICU acquired neuromyopathy].

    PubMed

    Gueret, G; Guillouet, M; Vermeersch, V; Guillard, E; Talarmin, H; Nguyen, B-V; Rannou, F; Giroux-Metges, M-A; Pennec, J-P; Ozier, Y

    2013-09-01

    ICU acquired neuromyopathy (IANM) is the most frequent neurological pathology observed in ICU. Nerve and muscle defects are merged with neuromuscular junction abnormalities. Its physiopathology is complex. The aim is probably the redistribution of nutriments and metabolism towards defense against sepsis. The main risk factors are sepsis, its severity and its duration of evolution. IANM is usually diagnosed in view of difficulties in weaning from mechanical ventilation, but electrophysiology may allow an earlier diagnosis. There is no curative therapy, but early treatment of sepsis, glycemic control as well as early physiotherapy may decrease its incidence. The outcomes of IANM are an increase in morbi-mortality and possibly long-lasting neuromuscular abnormalities as far as tetraplegia. PMID:23958176

  5. CNS Anticancer Drug Discovery and Development Conference White Paper.

    PubMed

    Levin, Victor A; Tonge, Peter J; Gallo, James M; Birtwistle, Marc R; Dar, Arvin C; Iavarone, Antonio; Paddison, Patrick J; Heffron, Timothy P; Elmquist, William F; Lachowicz, Jean E; Johnson, Ted W; White, Forest M; Sul, Joohee; Smith, Quentin R; Shen, Wang; Sarkaria, Jann N; Samala, Ramakrishna; Wen, Patrick Y; Berry, Donald A; Petter, Russell C

    2015-11-01

    Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward. PMID:26403167

  6. Nanotechnological advances for the delivery of CNS therapeutics.

    PubMed

    Wong, Ho Lun; Wu, Xiao Yu; Bendayan, Reina

    2012-05-15

    Effective non-invasive treatment of neurological diseases is often limited by the poor access of therapeutic agents into the central nervous system (CNS). The majority of drugs and biotechnological agents do not readily permeate into brain parenchyma due to the presence of two anatomical and biochemical dynamic barriers: the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Therefore, one of the most significant challenges facing CNS drug development is the availability of effective brain targeting technology. Recent advances in nanotechnology have provided promising solutions to this challenge. Several nanocarriers ranging from the more established systems, e.g. polymeric nanoparticles, solid lipid nanoparticles, liposomes, micelles to the newer systems, e.g. dendrimers, nanogels, nanoemulsions and nanosuspensions have been studied for the delivery of CNS therapeutics. Many of these nanomedicines can be effectively transported across various in vitro and in vivo BBB models by endocytosis and/or transcytosis, and demonstrated early preclinical success for the management of CNS conditions such as brain tumors, HIV encephalopathy, Alzheimer's disease and acute ischemic stroke. Future development of CNS nanomedicines need to focus on increasing their drug-trafficking performance and specificity for brain tissue using novel targeting moieties, improving their BBB permeability and reducing their neurotoxicity. PMID:22100125

  7. B4GALT6 regulates astrocyte activation during CNS inflammation

    PubMed Central

    Mayo, Lior; Trauger, Sunia A.; Blain, Manon; Nadeau, Meghan; Patel, Bonny; Alvarez, Jorge I.; Mascanfroni, Ivan D.; Yeste, Ada; Kivisäkk, Pia; Kallas, Keith; Ellezam, Benjamin; Bakshi, Rohit; Prat, Alexandre; Antel, Jack P.; Weiner, Howard L.; Quintana, Francisco J.

    2014-01-01

    Astrocytes play complex roles in the response to trauma, infection or inflammation in the central nervous system (CNS). Thus, it is important to characterize the mechanisms regulating astrocyte function, as well as potential targets for the therapeutic modulation of astrocyte activity. Here we report that lactosylceramide (LacCer) levels are up-regulated in the CNS during chronic experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). We found that LacCer synthesized by β-1,4-galactosyltransferase 6 (B4GALT6) in astrocytes acts in an autocrine manner to trigger transcriptional programs that promote the recruitment and activation of CNS-infiltrating monocytes and microglia, and neurodegeneration. We also detected increased B4GALT6 expression and LacCer levels in CNS MS lesions. Finally, the inhibition of LacCer synthesis suppressed local CNS innate immunity and neurodegeneration in EAE, and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 is a potential therapeutic target for MS and other neuroinflammatory disorders. PMID:25216636

  8. Amyloid-β efflux from the CNS into the plasma

    PubMed Central

    Roberts, Kaleigh Filisa; Elbert, Donald L.; Kasten, Tom P.; Patterson, Bruce W.; Sigurdson, Wendy C.; Connors, Rose E.; Ovod, Vitaliy; Munsell, Ling Y.; Mawuenyega, Kwasi G.; Miller-Thomas, Michelle M.; Moran, Christopher J.; Cross, Dewitte T.; Derdeyn, Colin P.; Bateman, Randall J.

    2015-01-01

    Objective The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed in order to determine if transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS). Methods Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing Inferior Petrosal Sinus Sampling (IPSS). For each plasma sample, Aβ concentration was assessed by three assays and the venous to arterial Aβ concentration ratios were determined. Results Aβ concentration was increased by ~7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aβ concentration compared to arterial blood concentration. Interpretation Our results are consistent with clearance of CNS-derived Aβ into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aβ across the blood-brain barrier accounts for ~25% of Aβ clearance, and reabsorption of cerebrospinal fluid Aβ accounts for ~25% of the total CNS Aβ clearance in humans. PMID:25205593

  9. Bovine-associated CNS species resist phagocytosis differently

    PubMed Central

    2013-01-01

    Background Coagulase-negative staphylococci (CNS) cause usually subclinical or mild clinical bovine mastitis, which often remains persistent. Symptoms are usually mild, mostly only comprising slight changes in the appearance of milk and possibly slight swelling. However, clinical mastitis with severe signs has also been reported. The reasons for the differences in clinical expression are largely unknown. Macrophages play an important role in the innate immunity of the udder. This study examined phagocytosis and killing by mouse macrophage cells of three CNS species: Staphylococcus chromogenes (15 isolates), Staphylococcus agnetis (6 isolates) and Staphylococcus simulans (15 isolates). Staphylococcus aureus (7 isolates) was also included as a control. Results All the studied CNS species were phagocytosed by macrophages, but S. simulans resisted phagocytosis more effectively than the other CNS species. Only S. chromogenes was substantially killed by macrophages. Significant variations between isolates were seen in both phagocytosis and killing by macrophages and were more common in the killing assays. Significant differences between single CNS species and S. aureus were observed in both assays. Conclusion This study demonstrated that differences in the phagocytosis and killing of mastitis-causing staphylococci by macrophages exist at both the species and isolate level. PMID:24207012

  10. Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats.

    PubMed

    Nikodemova, Maria; Small, Alissa L; Smith, Stephanie M C; Mitchell, Gordon S; Watters, Jyoti J

    2014-09-01

    Activation of microglia, CNS resident immune cells, is a pathological hallmark of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons. Despite evidence that microglia contribute to disease progression, the exact role of these cells in ALS pathology remains unknown. We immunomagnetically isolated microglia from different CNS regions of SOD1(G93A) rats at three different points in disease progression: presymptomatic, symptom onset and end-stage. We observed no differences in microglial number or phenotype in presymptomatic rats compared to wild-type controls. Although after disease onset there was no macrophage infiltration, there were significant increases in microglial numbers in the spinal cord, but not cortex. At disease end-stage, microglia were characterized by high expression of galectin-3, osteopontin and VEGF, and concomitant downregulated expression of TNFα, IL-6, BDNF and arginase-1. Flow cytometry revealed the presence of at least two phenotypically distinct microglial populations in the spinal cord. Immunohistochemistry showed that galectin-3/osteopontin positive microglia were restricted to the ventral horns of the spinal cord, regions with severe motor neuron degeneration. End-stage SOD1(G93A) microglia from the cortex, a less affected region, displayed similar gene expression profiles to microglia from wild-type rats, and displayed normal responses to systemic inflammation induced by LPS. On the other hand, end-stage SOD1(G93A) spinal microglia had blunted responses to systemic LPS suggesting that in addition to their phenotypic changes, they may also be functionally impaired. Thus, after disease onset, microglia acquired unique characteristics that do not conform to typical M1 (inflammatory) or M2 (anti-inflammatory) phenotypes. This transformation was observed only in the most affected CNS regions, suggesting that overexpression of mutated hSOD1 is not sufficient to trigger these changes in microglia. These

  11. Synaptogenesis in the CNS: An Odyssey from Wiring Together to Firing Together

    PubMed Central

    Munno, David W; Syed, Naweed I

    2003-01-01

    To acquire a better comprehension of nervous system function, it is imperative to understand how synapses are assembled during development and subsequently altered throughout life. Despite recent advances in the fields of neurodevelopment and synaptic plasticity, relatively little is known about the mechanisms that guide synapse formation in the central nervous system (CNS). Although many structural components of the synaptic machinery are pre-assembled prior to the arrival of growth cones at the site of their potential targets, innumerable changes, central to the proper wiring of the brain, must subsequently take place through contact-mediated cell-cell communications. Identification of such signalling molecules and a characterization of various events underlying synaptogenesis are pivotal to our understanding of how a brain cell completes its odyssey from ‘wiring together to firing together’. Here we attempt to provide a comprehensive overview that pertains directly to the cellular and molecular mechanisms of selection, formation and refinement of synapses during the development of the CNS in both vertebrates and invertebrates. PMID:12897180

  12. Primary CNS T-cell Lymphomas: A Clinical, Morphologic, Immunophenotypic, and Molecular Analysis.

    PubMed

    Menon, Madhu P; Nicolae, Alina; Meeker, Hillary; Raffeld, Mark; Xi, Liqiang; Jegalian, Armin G; Miller, Douglas C; Pittaluga, Stefania; Jaffe, Elaine S

    2015-12-01

    Primary central nervous system (CNS) lymphomas are relatively rare with the most common subtype being diffuse large B-cell lymphoma. Primary CNS T-cell lymphomas (PCNSTL) account for <5% of CNS lymphomas. We report the clinical, morphologic, immunophenotypic, and molecular characteristics of 18 PCNSTLs. Fifteen cases were classified as peripheral T-cell lymphoma, not otherwise specified, 2 of which were of γδ T-cell derivation and 1 was TCR silent; there was 1 anaplastic large cell lymphoma, ALK-positive and 2 anaplastic large cell lymphoma, ALK-negative. Median age was 58.5 years (range, 21 to 81 y), with an M:F ratio of 11:7. Imaging results showed that 15 patients had supratentorial lesions. Regardless of subtype, necrosis and perivascular cuffing of tumor cells were frequently observed (11/18 cases). CD3 was positive in all cases but 1; 10/17 were CD8-positive, and 5/17 were CD4-positive. Most cases studied had a cytotoxic phenotype with expression of TIA1 (13/15) and granzyme-B (9/13). Polymerase chain reaction analysis of T-cell receptor γ rearrangement confirmed a T-cell clone in 14 cases with adequate DNA quality. Next-generation sequencing showed somatic mutations in 36% of cases studied; 2 had >1 mutation, and none showed overlapping mutations. These included mutations in DNMT3A, KRAS, JAK3, STAT3, STAT5B, GNB1, and TET2 genes, genes implicated previously in other T-cell neoplasms. The outcome was heterogenous; 2 patients are alive without disease, 4 are alive with disease, and 6 died of disease. In conclusion, PCNSTLs are histologically and genomically heterogenous with frequent phenotypic aberrancy and a cytotoxic phenotype in most cases. PMID:26379152

  13. Disruption of Microtubule Integrity Initiates Mitosis during CNS Repair

    PubMed Central

    Bossing, Torsten; Barros, Claudia S.; Fischer, Bettina; Russell, Steven; Shepherd, David

    2012-01-01

    Summary Mechanisms of CNS repair have vital medical implications. We show that traumatic injury to the ventral midline of the embryonic Drosophila CNS activates cell divisions to replace lost cells. A pilot screen analyzing transcriptomes of single cells during repair pointed to downregulation of the microtubule-stabilizing GTPase mitochondrial Rho (Miro) and upregulation of the Jun transcription factor Jun-related antigen (Jra). Ectopic Miro expression can prevent midline divisions after damage, whereas Miro depletion destabilizes cortical β-tubulin and increases divisions. Disruption of cortical microtubules, either by chemical depolymerization or by overexpression of monomeric tubulin, triggers ectopic mitosis in the midline and induces Jra expression. Conversely, loss of Jra renders midline cells unable to replace damaged siblings. Our data indicate that upon injury, the integrity of the microtubule cytoskeleton controls cell division in the CNS midline, triggering extra mitosis to replace lost cells. The conservation of the identified molecules suggests that similar mechanisms may operate in vertebrates. PMID:22841498

  14. NanoART, neuroAIDS and CNS drug delivery

    PubMed Central

    Nowacek, Ari; Gendelman, Howard E

    2009-01-01

    A broad range of nanomedicines is being developed to improve drug delivery for CNS disorders. The structure of the blood–brain barrier (BBB), the presence of efflux pumps and the expression of metabolic enzymes pose hurdles for drug-brain entry. Nanoformulations can circumvent the BBB to improve CNS-directed drug delivery by affecting such pumps and enzymes. Alternatively, they can be optimized to affect their size, shape, and protein and lipid coatings to facilitate drug uptake, release and ingress across the barrier. This is important as the brain is a sanctuary for a broad range of pathogens including HIV-1. Improved drug delivery to the CNS would affect pharmacokinetic and drug biodistribution properties. This article focuses on how nanotechnology can serve to improve the delivery of antiretroviral medicines, termed nanoART, across the BBB and affect the biodistribution and clinical benefit for HIV-1 disease. PMID:19572821

  15. How Do Meningeal Lymphatic Vessels Drain the CNS?

    PubMed

    Raper, Daniel; Louveau, Antoine; Kipnis, Jonathan

    2016-09-01

    The many interactions between the nervous and the immune systems, which are active in both physiological and pathological states, have recently become more clearly delineated with the discovery of a meningeal lymphatic system capable of carrying fluid, immune cells, and macromolecules from the central nervous system (CNS) to the draining deep cervical lymph nodes. However, the exact localization of the meningeal lymphatic vasculature and the path of drainage from the cerebrospinal fluid (CSF) to the lymphatics remain poorly understood. Here, we discuss the potential differences between peripheral and CNS lymphatic vessels and examine the purported mechanisms of CNS lymphatic drainage, along with how these may fit into established patterns of CSF flow. PMID:27460561

  16. Therapeutic immune clearance of rabies virus from the CNS

    PubMed Central

    Hooper, D Craig; Roy, Anirban; Kean, Rhonda B; Phares, Timothy W; Barkhouse, Darryll A

    2011-01-01

    The long-held concept that rabies infection is lethal in humans once the causative rabies virus has reached the CNS has been called into question by the recent survival of a number of patients with clinical rabies. Studies in animal models provide insight into why survival from a rabies virus infection that has spread to the CNS is possible and the immune mechanisms involved. In the CNS, both innate mechanisms capable of inhibiting virus replication and the activity of infiltrating rabies virus-specific T and B cells with the capacity to clear the virus are required. Deficiencies in the induction of either aspect of rabies immunity can lead to lethal consequences but may be overcome by novel approaches to active and passive immunization. PMID:21686076

  17. BMP3 expression in the adult rat CNS.

    PubMed

    Yamashita, Kanna; Mikawa, Sumiko; Sato, Kohji

    2016-07-15

    Bone morphogenetic protein-3 (BMP3) is a very unique member of the TGF-β superfamily, because it functions as an antagonist to both the canonical BMP and activin pathways and plays important roles in multiple biological events. Although BMP3 expression has been described in the early development of the kidney, intestine and bone, little information is available for BMP3 expression in the central nervous system (CNS). We, thus, investigated BMP3 expression in the adult rat CNS using immunohistochemistry. BMP3 was intensely expressed in most neurons and their axons. Furthermore, we found that astrocytes and ependymal cells also express BMP3 protein. These data indicate that BMP3 is widely expressed throughout the adult CNS, and its abundant expression in the adult brain strongly supports the idea that BMP3 plays important roles in the adult brain. PMID:27130896

  18. Human C-reactive protein impedes entry of leptin into the CNS and attenuates its physiological actions in the CNS.

    PubMed

    Li, Jie; Wei, Dong; McCrory, Mark A; Szalai, Alexander J; Yang, Gangyi; Li, Ling; Li, Fanghong; Zhao, Allan Z

    2016-05-01

    Defective central leptin signalling and impaired leptin entry into the CNS (central nervous system) represent two important aspects of leptin resistance in obesity. In the present study, we tested whether circulating human CRP (C-reactive protein) not only diminishes signalling of leptin within the CNS, but also impedes this adipokine's access to the CNS. Peripheral infusion of human CRP together with co-infused human leptin was associated with significantly decreased leptin content in the CSF of ob/ob mice. Furthermore, following peripheral infusion of human leptin, the CSF (cerebrospinal fluid) concentration of leptin in transgenic mice overexpressing human CRP was sharply lower than that achieved in similarly infused wild-type mice. Administration of LPS (lipopolysaccharide) to human CRP-transgenic mice dramatically elevated the concentrations of human CRP in the CSF. The i.c.v. (intracerebroventricular) delivery of human CRP into the lateral ventricles of ob/ob mice blocked the satiety and weight-reducing actions of human leptin, but not those of mouse leptin. I.c.v. injection of human CRP abolished hypothalamic signalling by human leptin, and ameliorated the effects of leptin on the expression of NPY (neuropeptide Y), AgRP (Agouti-related protein), POMC (pro-opiomelanocortin) and SOCS-3 (suppressor of cytokine signalling 3). Human CRP can impede the access of leptin to the CNS, and elevation of human CRP within the CNS can have a negative impact on the physiological actions of leptin. PMID:26933237

  19. ICAM-1 induction in the mouse CNS following irradiation.

    PubMed

    Olschowka, J A; Kyrkanides, S; Harvey, B K; O'Banion, M K; Williams, J P; Rubin, P; Hansen, J T

    1997-12-01

    Injury to the central nervous system (CNS) results in inflammation, increased trafficking of leukocytes into the CNS, induction of cytokines, and exacerbation of the primary injury. The increased trafficking of neutrophils into the CNS has been described following a number of injury models including stab, stroke, and excitotoxin-induced injury. This enhanced trafficking has largely been ascribed to the adhesion molecule intercellular adhesion molecule-1 (ICAM-1, CD54). In the current study, we wished to determine if the inflammation caused by irradiation of the CNS resulted in a similar induction of ICAM-1. C3H/HeJ mice were irradiated using gamma irradiation aimed over the right cerebral hemisphere. The relative induction of ICAM-1 mRNA levels was determined using quantitative RT-PCR 6 hours following irradiation with either 0, 5, 15, 25 or 35 Gy. ICAM-1 message was seen to exhibit a normal dose response curve with increasing mRNA levels seen at 15 Gy and higher. To determine the cellular distribution of the ICAM-1 protein following irradiation, mice were sacrificed at 4 hrs, 24 hrs, 48 hrs and 7 days following 25 Gy irradiation and the tissue was processed for ICAM-1 immunocytochemistry. ICAM-1 staining was seen to increase in both endothelial cells and astrocytes beginning as early as 4 hrs. The staining intensity continued to increase throughout the 7 day period observed. Together, these results suggest that irradiation of the CNS causes a rapid induction of both ICAM-1 mRNA and protein. This suggests that increased leukocyte trafficking into the CNS may exacerbate the inflammation induced by radiation injury. PMID:9512815

  20. Compartmental Intrathecal Radioimmunotherapy: Results for Treatment for Metastatic CNS Neuroblastoma

    PubMed Central

    Kramer, Kim; Kushner, Brian H.; Modak, Shakeel; Pandit-Taskar, Neeta; Smith-Jones, Peter; Zanzonico, Pat; Humm, John L.; Xu, Hong; Wolden, Suzanne L.; Souweidane, Mark M.; Larson, Steven M.; Cheung, Nai-Kong V.

    2012-01-01

    Innovation in the management of brain metastases is needed. We evaluated the addition of compartmental intrathecal antibody-based radioimmunotherapy (cRIT) in patients with recurrent metastatic central nervous system (CNS) neuroblastoma following surgery, craniospinal irradiation, and chemotherapy. 21 patients treated for recurrent neuroblastoma metastatic to the CNS received a cRIT-containing salvage regimen incorporating intrathecal 131I-monoclonal antibodies (MoAbs) targeting GD2 or B7H3 following surgery and radiation. Most patients also received outpatient craniospinal irradiation, 3F8/GMCSF immunotherapy, 13-cis-retinoic acid and oral temozolomide for systemic control. Seventeen of 21 cRIT-salvage patients are alive 7-74 months (median 33) since CNS relapse, with all 17 remaining free of CNS neuroblastoma. One patient died of infection at 22 months with no evidence of disease at autopsy, and one of lung and bone marrow metastases at 15 months, and one of progressive bone marrow disease at 30 months. The cRIT-salvage regimen was well tolerated, notable for myelosuppression minimized by stem cell support (n=5), and biochemical hypothyroidism (n=5). One patient with a 7-year history of metastatic neuroblastoma is in remission from MLL-associated secondary leukemia. This is significantly improved to published results with non-cRIT based where relapsed CNS NB has a median time to death of approximately 6 months. The cRIT-salvage regimen for CNS metastases was well tolerated by young patients, despite their prior history of intensive cytotoxic therapies. It has the potential to increase survival with better than expected quality of life. PMID:19890606

  1. Intrinsic and acquired resistance mechanisms in enterococcus

    PubMed Central

    Hollenbeck, Brian L.; Rice, Louis B.

    2012-01-01

    Enterococci have the potential for resistance to virtually all clinically useful antibiotics. Their emergence as important nosocomial pathogens has coincided with increased expression of antimicrobial resistance by members of the genus. The mechanisms underlying antibiotic resistance in enterococci may be intrinsic to the species or acquired through mutation of intrinsic genes or horizontal exchange of genetic material encoding resistance determinants. This paper reviews the antibiotic resistance mechanisms in Enterococcus faecium and Enterococcus faecalis and discusses treatment options. PMID:23076243

  2. Toll-like Receptor 4 in CNS Pathologies

    PubMed Central

    Buchanan, Madison M.; Hutchinson, Mark; Watkins, Linda R.; Yin, Hang

    2010-01-01

    The responses of the brain to infection, ischemia and trauma share remarkable similarities. These and other conditions of the CNS coordinate an innate immune response marked by activation of microglia, the macrophage-like cells of the nervous system. An important contributor to microglial activation is toll-like receptor 4 (TLR4), a pathogen-associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli. The present review traces new efforts to characterize and control the contribution of TLR4 to inflammatory etiologies of the nervous system. PMID:20402965

  3. Myelin-Associated Inhibitors in Axonal Growth After CNS Injury

    PubMed Central

    Geoffroy, Cédric G.; Zheng, Binhai

    2014-01-01

    There are multiple barriers to axonal growth after CNS injury. Myelin-associated inhibitors represent one group of barriers extrinsic to the injured neurons. Nogo, MAG and OMgp are three prototypical myelin inhibitors that signal through multiple neuronal receptors to exert growth inhibition. Targeting myelin inhibition alone modulates the compensatory sprouting of uninjured axons but the effect on the regeneration of injured axons is limited. Meanwhile, modulating sprouting, a naturally occurring repair mechanism, may be a more attainable therapeutic goal for promoting functional repair after CNS injury in the near term. PMID:24608164

  4. Acute Acquired Concomitant Esotropia

    PubMed Central

    Chen, Jingchang; Deng, Daming; Sun, Yuan; Shen, Tao; Cao, Guobin; Yan, Jianhua; Chen, Qiwen; Ye, Xuelian

    2015-01-01

    Abstract Acute acquired concomitant esotropia (AACE) is a rare, distinct subtype of esotropia. The purpose of this retrospective study was to describe the clinical characteristics and discuss the classification and etiology of AACE. Charts from 47 patients with AACE referred to our institute between October 2010 and November 2014 were reviewed. All participants underwent a complete medical history, ophthalmologic and orthoptic examinations, and brain and orbital imaging. Mean age at onset was 26.6 ± 12.2 years. Of the 18 cases with deviations ≤ 20 PD, 16 presented with diplopia at distance and fusion at near vision at the onset of deviation; differences between distance and near deviations were < 8 PD; all cases except one were treated with prism and diplopia resolved. Of the 29 cases with deviations > 20 PD, 5 were mild hypermetropic with age at onset between 5 and 19 years, 16 were myopic, and 8 were emmetropic with age at onset > 12 years; 24 were surgically treated and 5 cases remained under observation; all 24 cases achieved normal retinal correspondence or fusion or stereopsis on postoperative day 1 in synoptophore; in 23 cases diplopia or visual confusion resolved postoperatively. Of the 47 cases, brain and orbital imaging in 2 cases revealed a tumor in the cerebellopontine angle and 1 case involved spinocerebellar ataxia as revealed by genetic testing. AACE in this study was characterized by a sudden onset of concomitant nonaccommodative esotropia with diplopia or visual confusion at 5 years of age or older and the potential for normal binocular vision. We suggest that AACE can be divided into 2 subgroups consisting of patients with relatively small versus large angle deviations. Coexisting or underlying neurological diseases were infrequent in AACE. PMID:26705210

  5. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

    PubMed

    Sturm, Dominik; Orr, Brent A; Toprak, Umut H; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J; Balasubramanian, Gnanaprakash; Worst, Barbara C; Pajtler, Kristian W; Brabetz, Sebastian; Johann, Pascal D; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M; Remke, Marc; Phillips, Joanna J; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C; Schniederjan, Matthew J; Santi, Mariarita; Buccoliero, Anna M; Dahiya, Sonika; Kramm, Christof M; von Bueren, André O; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S; Taylor, Michael D; Jones, Chris; Jabado, Nada; Karajannis, Matthias A; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M; Ellison, David W; Korshunov, Andrey; Kool, Marcel

    2016-02-25

    Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. PMID:26919435

  6. PGJ2 Provides Prolonged CNS Stroke Protection by Reducing White Matter Edema

    PubMed Central

    Nicholson, James D.; Puche, Adam C.; Guo, Yan; Weinreich, Daniel; Slater, Bernard J.; Bernstein, Steven L.

    2012-01-01

    Few clinically effective approaches reduce CNS-white matter injury. After early in-vivo white matter infarct, NFκB-driven pro-inflammatory signals can amplify a relatively small amount of vascular damage, resulting in progressive endothelial dysfunction to create a severe ischemic lesion. This process can be minimized by 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), an analog of the metabolically active PGD2 metabolite. We evaluated PGJ2's effects and mechanisms using rodent anterior ischemic optic neuropathy (rAION); an in vivo white matter ischemia model. PGJ2 administration systemically administered either acutely or 5 hours post-insult results in significant neuroprotection, with stereologic evaluation showing improved neuronal survival 30 days post-infarct. Quantitative capillary vascular analysis reveals that PGJ2 improves perfusion at 1 day post-infarct by reducing tissue edema. Our results suggest that PGJ2 acts by reducing NFκB signaling through preventing p65 nuclear localization and inhibiting inflammatory gene expression. Importantly, PGJ2 showed no in vivo toxicity structurally as measured by optic nerve (ON) myelin thickness, functionally by ON-compound action potentials, on a cellular basis by oligodendrocyte precursor survival or changes in ON-myelin gene expression. PGJ2 may be a clinically useful neuroprotective agent for ON and other CNS infarcts involving white matter, with mechanisms of action enabling effective treatment beyond the currently considered maximal time for intervention. PMID:23284631

  7. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... confer control of X and therefore will file as an acquiring person. Because A held the plant prior to the... within two persons, “A” and “B.” Under this section, if V is to acquire corporation X, both “A” and “B... person. Examples: 1. Assume that person “Q” will acquire voting securities of corporation X held by...

  8. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... confer control of X and therefore will file as an acquiring person. Because A held the plant prior to the... within two persons, “A” and “B.” Under this section, if V is to acquire corporation X, both “A” and “B... person. Examples: 1. Assume that person “Q” will acquire voting securities of corporation X held by...

  9. CNS Multiparameter Optimization Approach: Is it in Accordance with Occam's Razor Principle?

    PubMed

    Raevsky, Oleg A

    2016-04-01

    A detailed analysis of the possibility of using the Multiparameter Optimization approach (MPO) for CNS/non-CNS classification of drugs was carried out. This work has shown that MPO descriptors are able to describe only part of chemical transport in the CNS connected with transmembrane diffusion. Hence the "intuitive" CNS MPO approach with arbitrary selection of descriptors and calculations of score functions, search of thresholds of classification, and absence of any chemometric procedures, leads to rather modest accuracy of CNS/non-CNS classification models. PMID:27491918

  10. Anaerobic function of CNS white matter declines with age.

    PubMed

    Hamner, Margaret A; Möller, Thomas; Ransom, Bruce R

    2011-04-01

    The mammalian central nervous system (CNS) is generally believed to be completely dependent on the presence of oxygen (O(2)) to maintain energy levels necessary for excitability. However, previous studies on CNS white matter (WM) have shown that a large subset of CNS-myelinated axons of mice aged 4 to 6 weeks remains excitable in the absence of O(2). We investigated whether this surprising WM tolerance to anoxia varied with age. Acutely isolated mouse optic nerve (MON), a purely myelinated WM tract, was studied electrophysiologically. Excitability in the MONs from 1-month-, 4-month-, and 8-month-old mice was assessed quantitatively as the area under the supramaximal compound action potential (CAP). Anoxia-resistant WM function declined with age. After 60  minutes of anoxia, ∼23% of the CAP remained in 1-month-old mice, 8% in 4-month-old mice, and ∼0 in the 8-month-old group. Our results indicated that although some CNS axons function anaerobically in young adult animals, they lose this ability in later adulthood. This finding may help explain the clinical impression that favorable outcome after stroke and other brain injuries declines with age. PMID:21179073

  11. CaMKIIβ regulates oligodendrocyte maturation and CNS myelination.

    PubMed

    Waggener, Christopher T; Dupree, Jeffrey L; Elgersma, Ype; Fuss, Babette

    2013-06-19

    CNS myelination and the maturation of the myelinating cells of the CNS, namely oligodendrocytes, are thought to be regulated by molecular mechanisms controlling the actin cytoskeleton. However, the exact nature of these mechanisms is currently only poorly understood. Here we assessed the role of calcium/calmodulin-dependent kinase type II (CaMKII), in particular CaMKIIβ, in oligodendrocyte maturation and CNS myelination. Using in vitro culture studies, our data demonstrate that CaMKIIβ is critical for the proper morphological maturation of differentiating oligodendrocytes, an aspect of oligodendrocyte maturation that is mediated to a large extent by changes in the cellular cytoskeleton. Furthermore, our data provide evidence for an actin-cytoskeleton-stabilizing role of CaMKIIβ in differentiating oligodendrocytes. Using Camk2b knock-out and Camk2b(A303R) mutant mice, our data revealed an in vivo functional role of CaMKIIβ in regulating myelin thickness that may be mediated by a non-kinase-catalytic activity. Our data point toward a critical role of CaMKIIβ in regulating oligodendrocyte maturation and CNS myelination via an actin-cytoskeleton-regulatory mechanism. PMID:23785157

  12. ELECTROSTATIC CHARGE STIMULATES OXIDATIVE STRESS IN CNS MICROGLIA.

    EPA Science Inventory

    Nanometer size particles carry free radical activity on their surface and can create oxidative stress (OS)-mediated inflammatory changes upon impact. The oxidative burst signals the activation of phage-lineage cells such as peripheral macrophages, Kupffer cells and CNS microgl...

  13. Mechanisms underlying sexual and affiliative behaviors of mice: relation to generalized CNS arousal

    PubMed Central

    Shelley, Deborah N.; Choleris, Elena; Kavaliers, Martin

    2006-01-01

    The field of social neuroscience has grown dramatically in recent years and certain social responses have become amenable to mechanistic investigations. Toward that end, there has been remarkable progress in determining mechanisms for a simple sexual behavior, lordosis behavior. This work has proven that specific hormone-dependent biochemical reactions in specific parts of the mammalian brain regulate a biologically important behavior. On one hand, this sex behavior depends on underlying mechanisms of CNS arousal. On the other hand, it serves as a prototypical social behavior. The same sex hormones and the genes that encode their receptors as are involved in lordosis, also affect social recognition. Here we review evidence for a micronet of genes promoting social recognition in mice and discuss their biological roles. PMID:18985112

  14. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... acquired person is the pre-acquisition ultimate parent entity of the entity. (ii) The value of an... directors of B. A is deemed to be acquiring all of the assets of B as a result. (g) Transfers of patent... transfer of patent rights covered by this paragraph constitutes an asset acquisition; and (3) Patent...

  15. [Acquired aplastic anemia].

    PubMed

    Yamazaki, Hirohito

    2016-02-01

    Idiopathic aplastic anemia (AA) is an autoimmune disease caused by T cells. An increase in the percentage of glycosylphosphatidylinositol-anchored protein-deficient cells and the presence of HLA allele-lacking leukocytes due to 6pUPD provide indirect evidence that T cells contribute to the pathophysiology of AA. Recent studies have revealed the presence of somatic mutations in MDS and/or AML candidate genes in one third of AA patients. Current treatment topics include the efficacy of eltrombopag for AA found to be refractory to immunosuppressive therapy as well as for newly diagnosed AA when administered in combination with ATG and cyclosporine. Furthermore, improved outcomes of allogeneic bone marrow transplantation from unrelated donors using reduced-intensity conditioning regimens have been obtained with eltrombopag. Fludarabine-based regimens are now the mainstream approach for preconditioning and have lowered the transplant-related mortality rate. However, new problems such as mixed chimerism and secondary graft failure have arisen. Attempts to prevent GVHD more efficiently by including ATG and alemtuzumab in the preconditioning regimen are being investigated. PMID:26935624

  16. Regeneration of Zebrafish CNS: Adult Neurogenesis

    PubMed Central

    Ghosh, Sukla; Hui, Subhra Prakash

    2016-01-01

    Regeneration in the animal kingdom is one of the most fascinating problems that have allowed scientists to address many issues of fundamental importance in basic biology. However, we came to know that the regenerative capability may vary across different species. Among vertebrates, fish and amphibians are capable of regenerating a variety of complex organs through epimorphosis. Zebrafish is an excellent animal model, which can repair several organs like damaged retina, severed spinal cord, injured brain and heart, and amputated fins. The focus of the present paper is on spinal cord regeneration in adult zebrafish. We intend to discuss our current understanding of the cellular and molecular mechanism(s) that allows formation of proliferating progenitors and controls neurogenesis, which involve changes in epigenetic and transcription programs. Unlike mammals, zebrafish retains radial glia, a nonneuronal cell type in their adult central nervous system. Injury induced proliferation involves radial glia which proliferate, transcribe embryonic genes, and can give rise to new neurons. Recent technological development of exquisite molecular tools in zebrafish, such as cell ablation, lineage analysis, and novel and substantial microarray, together with advancement in stem cell biology, allowed us to investigate how progenitor cells contribute to the generation of appropriate structures and various underlying mechanisms like reprogramming. PMID:27382491

  17. Regeneration of Zebrafish CNS: Adult Neurogenesis.

    PubMed

    Ghosh, Sukla; Hui, Subhra Prakash

    2016-01-01

    Regeneration in the animal kingdom is one of the most fascinating problems that have allowed scientists to address many issues of fundamental importance in basic biology. However, we came to know that the regenerative capability may vary across different species. Among vertebrates, fish and amphibians are capable of regenerating a variety of complex organs through epimorphosis. Zebrafish is an excellent animal model, which can repair several organs like damaged retina, severed spinal cord, injured brain and heart, and amputated fins. The focus of the present paper is on spinal cord regeneration in adult zebrafish. We intend to discuss our current understanding of the cellular and molecular mechanism(s) that allows formation of proliferating progenitors and controls neurogenesis, which involve changes in epigenetic and transcription programs. Unlike mammals, zebrafish retains radial glia, a nonneuronal cell type in their adult central nervous system. Injury induced proliferation involves radial glia which proliferate, transcribe embryonic genes, and can give rise to new neurons. Recent technological development of exquisite molecular tools in zebrafish, such as cell ablation, lineage analysis, and novel and substantial microarray, together with advancement in stem cell biology, allowed us to investigate how progenitor cells contribute to the generation of appropriate structures and various underlying mechanisms like reprogramming. PMID:27382491

  18. Electroporation of cDNA/Morpholinos to targeted areas of embryonic CNS in Xenopus

    PubMed Central

    Falk, Julien; Drinjakovic, Jovana; Leung, Kin Mei; Dwivedy, Asha; Regan, Aoife G; Piper, Michael; Holt, Christine E

    2007-01-01

    Background Blastomere injection of mRNA or antisense oligonucleotides has proven effective in analyzing early gene function in Xenopus. However, functional analysis of genes involved in neuronal differentiation and axon pathfinding by this method is often hampered by earlier function of these genes during development. Therefore, fine spatio-temporal control of over-expression or knock-down approaches is required to specifically address the role of a given gene in these processes. Results We describe here an electroporation procedure that can be used with high efficiency and low toxicity for targeting DNA and antisense morpholino oligonucleotides (MOs) into spatially restricted regions of the Xenopus CNS at a critical time-window of development (22–50 hour post-fertilization) when axonal tracts are first forming. The approach relies on the design of "electroporation chambers" that enable reproducible positioning of fixed-spaced electrodes coupled with accurate DNA/MO injection. Simple adjustments can be made to the electroporation chamber to suit the shape of different aged embryos and to alter the size and location of the targeted region. This procedure can be used to electroporate separate regions of the CNS in the same embryo allowing separate manipulation of growing axons and their intermediate and final targets in the brain. Conclusion Our study demonstrates that electroporation can be used as a versatile tool to investigate molecular pathways involved in axon extension during Xenopus embryogenesis. Electroporation enables gain or loss of function studies to be performed with easy monitoring of electroporated cells. Double-targeted transfection provides a unique opportunity to monitor axon-target interaction in vivo. Finally, electroporated embryos represent a valuable source of MO-loaded or DNA transfected cells for in vitro analysis. The technique has broad applications as it can be tailored easily to other developing organ systems and to other organisms by

  19. Myelin damage and repair in pathologic CNS: challenges and prospects

    PubMed Central

    Alizadeh, Arsalan; Dyck, Scott M.; Karimi-Abdolrezaee, Soheila

    2015-01-01

    Injury to the central nervous system (CNS) results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells and neural stem/progenitor cells contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i) low levels of factors that promote oligodendrogenesis; (ii) cell death among newly generated oligodendrocytes, (iii) inhibitory factors in the post-injury milieu that impede remyelination, and (iv) deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for

  20. Astrocytic TIMP-1 Promotes Oligodendrocyte Differentiation and Enhances CNS Myelination

    PubMed Central

    Moore, Craig S.; Milner, Richard; Nishiyama, Akiko; Frausto, Ricardo F.; Serwanski, David R.; Pagarigan, Roberto R.; Whitton, J. Lindsay; Miller, Robert H.; Crocker, Stephen J.

    2011-01-01

    Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an extracellular protein and endogenous regulator of matrix metalloproteinases (MMPs) secreted by astrocytes in response to CNS myelin injury. We have previously reported that adult TIMP-1KO mice exhibit poor myelin repair following demyelinating injury. This observation led us to hypothesize a role for TIMP-1 in oligodendrogenesis and CNS myelination. Herein, we demonstrate that compact myelin formation is significantly delayed in TIMP-1KO mice which coincided with dramatically reduced numbers of white matter astrocytes in the developing CNS. Analysis of differentiation in CNS progenitor cells (neurosphere) cultures from TIMP-1KO mice revealed a specific deficit of NG2+ oligodendrocyte progenitor cells. Application of rmTIMP-1 to TIMP-1KO neurosphere cultures evoked a dose-dependent increase in NG2+ cell numbers, while treatment with GM6001, a potent broad spectrum MMP inhibitor did not. Similarly, administration of recombinant murine TIMP-1 (rmTIMP-1) to A2B5+ immunopanned oligodendrocyte progenitors significantly increased the number of differentiated O1+ oligodendrocytes, while antisera to TIMP-1 reduced oligodendrocyte numbers. We also determined that A2B5+ oligodendrocyte progenitors grown in conditioned media derived from TIMP-1KO primary glial cultures resulted in reduced differentiation of mature O1+ oligodendrocytes. Finally, we report that addition of rmTIMP-1 to primary glial cultures resulted in a dose-dependent proliferative response of astrocytes. Together, these findings describe a previously uncharacterized role for TIMP-1 in the regulation of oligodendrocytes and astrocytes during development and provide a novel function for TIMP-1 on myelination in the developing CNS. PMID:21508247

  1. RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer.

    PubMed

    Ahlers, Katelin E; Chakravarti, Bandana; Fisher, Rory A

    2016-05-01

    Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gαi/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target. PMID:27002730

  2. H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system (CNS-PNET) and pediatric glioblastomas: possible diagnostic and therapeutic implications?

    PubMed

    Gessi, Marco; Gielen, Gerrit H; Hammes, Jennifer; Dörner, Evelyn; Mühlen, Anja Zur; Waha, Andreas; Pietsch, Torsten

    2013-03-01

    Pediatric glioblastomas recently have been exon sequenced with evidence that approximately 30 % of cases harbour mutations of the histone H3.3 gene. Although studies to determinate their role in risk stratification are on-going, it remains to be determined whether H3.3 mutations could be found in other tumors such as pediatric primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) and whether the presence of H3.3 mutations in glioblastomas could be used as diagnostic tool in their differential diagnosis with CNS-PNETs. We performed a large mutational pyrosequencing-based screening on 123 pediatric glioblastomas and 33 CNS-PNET. The analysis revealed that 39/123 (31.7 %) glioblastomas carry H3.3 mutations. The K27M (AAG → ATG, lysine → methionine) mutation was found in 33 glioblastomas (26 %); the G34R (GGG → AGG, glycine → arginine) was observed in 6 glioblastomas (5.5 %). However, we also identified 4 of 33 cases (11 %) of CNS-PNETs harbouring a H3.3 G34R mutation. Multiplex ligation-dependent probe amplification analysis revealed PDGFR-alpha amplification and EGFR gain in two cases and N-Myc amplification in one case of H3.3 G34R mutated CNS-PNET. None of H3.3 mutated tumors presented a CDKN2A loss. In conclusion, because pediatric patients with glioblastoma and CNS-PNET are treated according to different therapeutic protocols, these findings may raise further concerns about the reliability of the histological diagnosis in the case of an undifferentiated brain tumor harbouring G34R H3.3 mutation. In this view, additional studies are needed to determine whether H3.3 G34 mutated CNS-PNET/glioblastomas may represent a defined tumor subtype. PMID:23354654

  3. Children Acquire Emotion Categories Gradually

    ERIC Educational Resources Information Center

    Widen, Sherri C.; Russell, James A.

    2008-01-01

    Some accounts imply that basic-level emotion categories are acquired early and quickly, whereas others imply that they are acquired later and more gradually. Our study examined this question for fear, happiness, sadness, and anger in the context of children's categorization of emotional facial expressions. Children (N=168, 2-5 years) first labeled…

  4. CNP is required for maintenance of axon-glia interactions at nodes of Ranvier in the CNS.

    PubMed

    Rasband, Matthew N; Tayler, Jane; Kaga, Yoshimi; Yang, Yang; Lappe-Siefke, Corinna; Nave, Klaus-Armin; Bansal, Rashmi

    2005-04-01

    Axoglial interactions underlie the clustering of ion channels and of cell adhesion molecules, regulate gene expression, and control cell survival. We report that Cnp1-null mice, lacking expression of the myelin protein cyclic nucleotide phosphodiesterase (CNP), have disrupted axoglial interactions in the central nervous system (CNS). Nodal sodium channels (Nav) and paranodal adhesion proteins (Caspr) are initially clustered normally, but become progressively disorganized with age. These changes are characterized by mislocalized Caspr immunostaining, combined with a decrease of clustered Na+ channels, and occur before axonal degeneration and microglial invasion, both prominent in older Cnp1-null mice. We suggest that CNP is a glial protein required for maintaining the integrity of paranodes and that disrupted axoglial signaling at this site underlies progressive axonal degeneration, observed later in the CNS of Cnp1-null mice. PMID:15657937

  5. Alterations of CNS structure & function by charged particle radiation & resultant oxidative stress

    NASA Astrophysics Data System (ADS)

    Nelson, Gregory; Chang, Polly; Favre, Cecile; Fike, John; Komarova, Natalia; Limoli, Charles; Mao, Xiao-Wen; Obenaus, Andre; Raber, Jacob; Spigelman, Igor; Soltesz, Ivan; Song, Sheng-Kwei; Stampanoni, Marco; Vlkolinsky, Roman; Wodarz, Dominik

    The NSCOR program project is transitioning from establishing the existence of CNS responses to low doses of charged particles, to an investigation of mechanisms underlying these changes and extending the irradiation paradigm to more space-like exposures. In earlier experiments we examined radiation responses of the mouse brain (hippocampus) following exposure to 250 MeV protons and 600 MeV/n iron ions. Our key findings on structural changes were: 1) Significant dose and time dependent loss of en-dothelial cells and microvessel network remodeling occurs suggesting that vascular insufficiency is produced. 2) Significant dose dependent losses of neural precursor cells were observed in a lineage specific pattern which may be associated with cognitive impairment. 3) Evaluation of DNA damage showed dose and time dependent accumulation of mutations with region-specific mutation structures and gene expression profiling demonstrated activation of neurotrophic and adhesion factors as well as chemokine receptors associated with inflammation. Our key find-ings on functional changes were: 1) Time and dose dependent modifications to neural output expressed as enhanced excitability but reduced synaptic efficacy and plasticity (including long term potentiation). 2) Intrinsic membrane properties of neurons were not significantly modi-fied by radiation exposure but pharmacological treatments demonstrated changes in inhibitory synapses. 3) MRI imaging visualized brain structural changes based on altered water diffu-sion properties and patterns were consistent with demyelination or gliosis. Our key findings on neurodegeneration and fidelity of homeostasis were: 1) APP23 transgenic mice exhibited accelerated APP-type electrophysiological pathology over several months. 2) Microvessel net-work changes following irradiation were suggestive of poor tissue oxygenation. 3) The ability of the brain to respond a controlled septic shock was altered by irradiation; the septic shock reactions

  6. Alterations of CNS structure & function by charged particle radiation & resultant oxidative stress

    NASA Astrophysics Data System (ADS)

    Nelson, Gregory; Chang, Polly; Favre, Cecile; Fike, John; Komarova, Natalia; Limoli, Charles; Mao, Xiao-Wen; Obenaus, Andre; Raber, Jacob; Spigelman, Igor; Soltesz, Ivan; Song, Sheng-Kwei; Stampanoni, Marco; Vlkolinsky, Roman; Wodarz, Dominik

    The NSCOR program project is transitioning from establishing the existence of CNS responses to low doses of charged particles, to an investigation of mechanisms underlying these changes and extending the irradiation paradigm to more space-like exposures. In earlier experiments we examined radiation responses of the mouse brain (hippocampus) following exposure to 250 MeV protons and 600 MeV/n iron ions. Our key findings on structural changes were: 1) Significant dose and time dependent loss of en-dothelial cells and microvessel network remodeling occurs suggesting that vascular insufficiency is produced. 2) Significant dose dependent losses of neural precursor cells were observed in a lineage specific pattern which may be associated with cognitive impairment. 3) Evaluation of DNA damage showed dose and time dependent accumulation of mutations with region-specific mutation structures and gene expression profiling demonstrated activation of neurotrophic and adhesion factors as well as chemokine receptors associated with inflammation. Our key find-ings on functional changes were: 1) Time and dose dependent modifications to neural output expressed as enhanced excitability but reduced synaptic efficacy and plasticity (including long term potentiation). 2) Intrinsic membrane properties of neurons were not significantly modi-fied by radiation exposure but pharmacological treatments demonstrated changes in inhibitory synapses. 3) MRI imaging visualized brain structural changes based on altered water diffu-sion properties and patterns were consistent with demyelination or gliosis. Our key findings on neurodegeneration and fidelity of homeostasis were: 1) APP23 transgenic mice exhibited accelerated APP-type electrophysiological pathology over several months. 2) Microvessel net-work changes following irradiation were suggestive of poor tissue oxygenation. 3) The ability of the brain to respond a controlled septic shock was altered by irradiation; the septic shock reactions

  7. Expression of the small heat shock protein family in the mouse CNS: differential anatomical and biochemical compartmentalization.

    PubMed

    Quraishe, S; Asuni, A; Boelens, W C; O'Connor, V; Wyttenbach, A

    2008-05-01

    The small heat shock proteins (sHsps) are a family of molecular chaperones defined by an alpha-crystallin domain that is important for sHsps oligomerization and chaperone activity. sHsps perform many physiological functions including the maintenance of the cellular cytoskeleton, the regulation of protein aggregation and modulate cell survival in a number of cell types including glial and neuronal cells. Many of these functions have been implicated in disease processes in the CNS and indeed sHsps are considered targets for disease therapy. Despite this, there is no study that systematically and comparatively characterized sHsps expression in the CNS. In the present study we have analyzed the expression of this gene family in the mouse brain by reverse-transcriptase polymerase chain reaction (RT-PCR), in situ hybridization and Western blotting. Gene expression analysis of the 10 known members of mammalian sHsps confirms the presence of 5 sHsps in the CNS. A distinct white matter specific expression pattern for HspB5 and overlapping expression of HspB1 and HspB8 in the lateral and dorsal ventricles of the brain is observed. We confirm protein expression of HspB1, HspB5, HspB6 and HspB8 in the brain. Further subcellular fractionation of brain and synaptosomes details a distinct subcompartment-specific association and detergent solubility of sHsps. This biochemical signature is indicative of an association with synaptic and other neural specializations. This observation will help one understand the functional role played by sHsps during physiology and pathology in the CNS. PMID:18384969

  8. Chd7 Cooperates with Sox10 and Regulates the Onset of CNS Myelination and Remyelination

    PubMed Central

    He, Danyang; Marie, Corentine; Zhao, Chuntao; Kim, Bongwoo; Wang, Jincheng; Deng, Yaqi; Clavairoly, Adrien; Frah, Magali; Wang, Haibo; He, Xuelian; Hmidan, Hatem; Jones, Blaise V.; Witte, David; Zalc, Bernard; Zhou, Xin; Choo, Daniel I.; Martin, Donna M.; Parras, Carlos; Lu, Q. Richard

    2016-01-01

    Mutations in CHD7, encoding ATP-dependent chromodomain-helicase-DNA-binding protein 7, in CHARGE syndrome leads to multiple congenital anomalies including craniofacial malformations, neurological dysfunction and growth delay. Currently, mechanisms underlying the CNS phenotypes remain poorly understood. Here, we show that Chd7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1, and is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses, coupled with transcriptome profiling, reveal that Chd7 interacts with Sox10 and targets the enhancers of key myelinogenic genes, and identify novel Chd7 targets including bone formation regulators Osterix/Sp7 and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, Chd7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages including oligodendrocytes and osteoblasts, pointing to the hitherto previously uncharacterized Chd7 functions in white matter pathogenesis in CHARGE syndrome. PMID:26928066

  9. Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS.

    PubMed

    Tran, Tracy S; Rubio, Maria E; Clem, Roger L; Johnson, Dontais; Case, Lauren; Tessier-Lavigne, Marc; Huganir, Richard L; Ginty, David D; Kolodkin, Alex L

    2009-12-24

    The majority of excitatory synapses in the mammalian CNS (central nervous system) are formed on dendritic spines, and spine morphology and distribution are critical for synaptic transmission, synaptic integration and plasticity. Here, we show that a secreted semaphorin, Sema3F, is a negative regulator of spine development and synaptic structure. Mice with null mutations in genes encoding Sema3F, and its holoreceptor components neuropilin-2 (Npn-2, also known as Nrp2) and plexin A3 (PlexA3, also known as Plxna3), exhibit increased dentate gyrus (DG) granule cell (GC) and cortical layer V pyramidal neuron spine number and size, and also aberrant spine distribution. Moreover, Sema3F promotes loss of spines and excitatory synapses in dissociated neurons in vitro, and in Npn-2(-/-) brain slices cortical layer V and DG GCs exhibit increased mEPSC (miniature excitatory postsynaptic current) frequency. In contrast, a distinct Sema3A-Npn-1/PlexA4 signalling cascade controls basal dendritic arborization in layer V cortical neurons, but does not influence spine morphogenesis or distribution. These disparate effects of secreted semaphorins are reflected in the restricted dendritic localization of Npn-2 to apical dendrites and of Npn-1 (also known as Nrp1) to all dendrites of cortical pyramidal neurons. Therefore, Sema3F signalling controls spine distribution along select dendritic processes, and distinct secreted semaphorin signalling events orchestrate CNS connectivity through the differential control of spine morphogenesis, synapse formation, and the elaboration of dendritic morphology. PMID:20010807

  10. Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination.

    PubMed

    He, Danyang; Marie, Corentine; Zhao, Chuntao; Kim, Bongwoo; Wang, Jincheng; Deng, Yaqi; Clavairoly, Adrien; Frah, Magali; Wang, Haibo; He, Xuelian; Hmidan, Hatem; Jones, Blaise V; Witte, David; Zalc, Bernard; Zhou, Xin; Choo, Daniel I; Martin, Donna M; Parras, Carlos; Lu, Q Richard

    2016-05-01

    Mutations in CHD7, encoding ATP-dependent chromodomain helicase DNA-binding protein 7, in CHARGE syndrome lead to multiple congenital anomalies, including craniofacial malformations, neurological dysfunction and growth delay. Mechanisms underlying the CNS phenotypes remain poorly understood. We found that Chd7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1 and is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses in mice, coupled with transcriptome profiling, revealed that Chd7 interacted with Sox10 and targeted the enhancers of key myelinogenic genes. These analyses identified previously unknown Chd7 targets, including bone formation regulators Osterix (also known as Sp7) and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, Chd7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages, including oligodendrocytes and osteoblasts, pointing to previously uncharacterized Chd7 functions in white matter pathogenesis in CHARGE syndrome. PMID:26928066

  11. Collagen IV is present in the developing CNS during Drosophila neurogenesis.

    PubMed

    Mirre, C; Le Parco, Y; Knibiehler, B

    1992-01-01

    By means of immunocytochemistry with a battery of specific antibodies, we describe the expression of the collagen IV chain produced by the gene DCg1 during the two phases of Drosophila neurogenesis. DgC1 was not expressed in neuronal tissues as shown by in situ hybridization, but the onset of its expression in cells of mesodermal origin was concomitant with the appearance of collagen IV on early axon pathways and peripheral nerve roots in the embryonic developing CNS. A similar situation was found during imaginal CNS development at metamorphosis, when collagen IV immunoreactivity was detected on centrifugal and centripetal nerve pathways, and specially on retinula axons that develop from the eye imaginal disc towards the lamina anlage in the brain optic lobe. Our results strongly suggest that collagen IV could be involved, together with other informative molecules of basement membranes, in a dynamic process of cell-matrix interactions during the establishment of initial axon pathways and neurite outgrowth in vivo. PMID:1613819

  12. Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase

    PubMed Central

    El-Amouri, Salim S; Dai, Mei; Han, Jing-Fen; Brady, Roscoe O; Pan, Dao

    2014-01-01

    Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-l-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application. PMID:25088464

  13. Normalization and improvement of CNS deficits in mice with Hurler syndrome after long-term peripheral delivery of BBB-targeted iduronidase.

    PubMed

    El-Amouri, Salim S; Dai, Mei; Han, Jing-Fen; Brady, Roscoe O; Pan, Dao

    2014-12-01

    Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-L-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application. PMID:25088464

  14. Adeno associated viral-mediated intraosseous labeling of bone marrow derived cells for CNS tracking.

    PubMed

    Selenica, Maj-Linda B; Reid, Patrick; Pena, Gabriela; Alvarez, Jennifer; Hunt, Jerry B; Nash, Kevin R; Morgan, Dave; Gordon, Marcia N; Lee, Daniel C

    2016-05-01

    Inflammation, including microglial activation in the CNS, is an important hallmark in many neurodegenerative diseases. Microglial stimuli not only impact the brain microenvironment by production and release of cytokines and chemokines, but also influence the activity of bone marrow derived cells and blood born macrophage populations. In many diseases including brain disorders and spinal cord injury, researchers have tried to harbor the neuroprotective and repair properties of these subpopulations. Hematopoietic bone marrow derived cells (BMDCs) are of great interest, especially during gene therapy because certain hematopoietic cell subpopulations traffic to the sites of injury and inflammation. The aim of this study was to develop a method of labeling endogenous bone marrow derived cells through intraosseous impregnation of recombinant adeno-associated virus (rAAV) or lentivirus. We utilized rAAV serotype 9 (rAAV-9) or lentivirus for gene delivery of green florescence protein (GFP) to the mouse bone marrow cells. Flow cytometry showed that both viruses were able to efficiently transduce mouse bone marrow cells in vivo. However, the rAAV9-GFP viral construct transduced BMDCs more efficiently than the lentivirus (11.2% vs. 6.8%), as indicated by cellular GFP expression. We also demonstrate that GFP labeled cells correspond to bone marrow cells of myeloid origin using CD11b as a marker. Additionally, we characterized the ability of bone marrow derived, GFP labeled cells to extravasate into the brain parenchyma upon acute and subchronic neuroinflammatory stimuli in the mouse CNS. Viral mediated over expression of chemokine (C-C motif) ligand 2 (CCL2) or intracranial injection of lipopolysaccharide (LPS) recruited GFP labeled BMDCs from the periphery into the brain parenchyma compared to vehicle treated mice. Altogether our findings demonstrate a useful method of labeling endogenous BMDCs via viral transduction and the ability to track subpopulations throughout the body

  15. Single Cell Electroporation Method for Mammalian CNS Neurons in Organotypic Slice Cultures

    NASA Astrophysics Data System (ADS)

    Uesaka, Naofumi; Hayano, Yasufumi; Yamada, Akito; Yamamoto, Nobuhiko

    Axon tracing is an essential technique to study the projection pattern of neurons in the CNS. Horse radish peroxidase and lectins have contributed to revealing many neural connection patterns in the CNS (Itaya and van Hoesen, 1982; Fabian and Coulter, 1985; Yoshihara, 2002). Moreover, a tracing method with fluorescent dye has enabled the observation of growing axons in living conditions, and demon strated a lot of developmental aspects in axon growth and guidance (Harris et al., 1987; O'Rourke and Fraser, 1990; Kaethner and Stuermer, 1992; Halloran and Kalil, 1994; Yamamoto et al., 1997). More recently, genetically encoded fluores cent proteins can be used as a powerful tool to observe various biological events. Several gene transfer techniques such as microinjection, biolistic gene gun, viral infection, lipofection and transgenic technology have been developed (Feng et al., 2000; Ehrengruber et al., 2001; O'Brien et al., 2001; Ma et al., 2002; Sahly et al., 2003). In particular, the electroporation technique was proved as a valuable tool, since it can be applied to a wide range of tissues and cell types with little toxicity and can be performed with relative technical easiness. Most methods, including a stand ard electroporation technique, are suitable for gene transfer to a large number of cells. However, this is not ideal for axonal tracing, because observation of individ ual axons is occasionally required. To overcome this problem, we have developed an electroporation method using glass micropipettes containing plasmid solutions and small current injection. Here we introduce the method in detail and exemplified results with some example applications and discuss its usefulness.

  16. Autoradiographic visualization of CNS receptors for vasoactive intestinal peptide

    SciTech Connect

    Shaffer, M.M.; Moody, T.W.

    1986-03-01

    Receptors for VIP were characterized in the rat CNS. /sup 125/I-VIP bound with high affinity to rat brain slices. Binding was time dependent and specific. Pharmacology studies indicated that specific /sup 125/I-VIP binding was inhibited with high affinity by VIP and low affinity by secretin and PHI. Using in vitro autoradiographic techniques high grain densities were present in the dentate gyrus, pineal gland, supraoptic and suprachiasmatic nuclei, superficial gray layer of the superior colliculus and the area postrema. Moderate grain densities were present in the olfactory bulb and tubercle, cerebral cortex, nucleus accumbens, caudate putamen, interstitial nucleus of the stria terminalis, paraventricular thalamic nucleus, medial amygdaloid nucleus, subiculum and the medial geniculate nucleus. Grains were absent in the corpus callosum and controls treated with 1 microM unlabeled VIP. The discrete regional distribution of VIP receptors suggest that it may function as an important modulator of neural activity in the CNS.

  17. Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

    PubMed Central

    Maze, Ian; Noh, Kyung-Min; Allis, C David

    2013-01-01

    Postmitotic neurons are subject to a vast array of environmental influences that require the nuclear integration of intracellular signaling events to promote a wide variety of neuroplastic states associated with synaptic function, circuit formation, and behavioral memory. Over the last decade, much attention has been paid to the roles of transcription and chromatin regulation in guiding fundamental aspects of neuronal function. A great deal of this work has centered on neurodevelopmental and adulthood plasticity, with increased focus in the areas of neuropharmacology and molecular psychiatry. Here, we attempt to provide a broad overview of chromatin regulation, as it relates to central nervous system (CNS) function, with specific emphasis on the modes of histone posttranslational modifications, chromatin remodeling, and histone variant exchange. Understanding the functions of chromatin in the context of the CNS will aid in the future development of pharmacological therapeutics aimed at alleviating devastating neurological disorders. PMID:22828751

  18. Cranial radiation necessary for CNS prophylaxis in pediatric NHL

    SciTech Connect

    Mandell, L.R.; Wollner, N.; Fuks, Z.

    1987-03-01

    The records of 95 consecutive children less than or equal to 21 years of age with previously untreated diffuse histology NHL registered in our protocols from 1978 to 1983 were reviewed. Seventy-nine patients were considered eligible for analysis. The histologic subtypes represented included lymphoblastic (LB) 37%; histiocytic (DHL) 29%; undifferentiated (DU) 19%; poorly differentiated (DPDL) 9%; and unclassified (UNHL) 6%. Distribution of the patients according to stage showed Stage I, 0%; Stage II, 11%; Stage III, 53%; Stage IV, 36%. Four different Memorial Hospital protocols for systemic chemotherapy were used (LSA2L2 73%; L10 9%; L17 10%; L17M 8%); however, the IT (intrathecal) chemotherapy was uniform (Methotrexate: 6.0-6.25 mg/M2 per treatment course) and was included in the induction, consolidation, and maintenance phases of all treatment protocols. Cranial radiation was included in the induction, consolidation, and maintenance phases of all treatment protocols. Cranial radiation was not included in the CNS prophylaxis program. The overall median time of follow-up was 43 months. The overall CNS relapse rate was 6.3%; however, the incidence of CNS lymphoma presenting as the first isolated site of relapse in patients in otherwise complete remission (minimum follow-up of 19 months with 97% of patients off treatment) was only 1/58 (1.7%). Our data suggest that IT chemotherapy when given in combination with modern aggressive systemic combination chemotherapy, and without cranial radiation appears to be a highly effective modality for CNS prophylaxis regardless of stage, histology, or bone marrow or mediastinal involvement. (Abstract Truncated)

  19. Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections.

    PubMed

    Krut, Jan Jessen; Zetterberg, Henrik; Blennow, Kaj; Cinque, Paola; Hagberg, Lars; Price, Richard W; Studahl, Marie; Gisslén, Magnus

    2013-02-01

    The cerebrospinal fluid (CSF) biomarker profile in Alzheimer's disease (AD) is characterized by decreased beta amyloid (Aβ(1-42)), increased total and hyperphosphorylated tau (t-tau and p-tau, respectively), which is a useful diagnostic tool and gives insight in the pathogenesis of AD. It is of importance to study how these biomarkers react in other CNS diseases; therefore, we decided to analyse amyloid and tau biomarkers in different CNS infections. We also included analysis of soluble amyloid precursor proteins (sAPPα and -β). CSF Aβ(1-42), sAPPα and -β, t-tau and p-tau were analysed in bacterial meningitis (n = 12), Lyme neuroborreliosis (n = 13), herpes simplex virus type 1 (HSV-1) encephalitis (n = 10), HIV-associated dementia (HAD) (n = 21), AD (n = 21) and healthy controls (n = 42). Concurrent with AD, Aβ(1-42) was decreased in all groups except neuroborreliosis compared to controls. HSV-1 encephalitis, bacterial meningitis and HAD showed lower concentrations of sAPPα and -β compared to AD. T-tau was increased in AD and HSV-1 encephalitis compared to all other groups. P-tau was higher in AD and HSV-1 encephalitis compared to bacterial meningitis, HAD and control. Decreased CSF Aβ(1-42), sAPPα and -β in various CNS infections imply an effect of neuroinflammation on amyloid metabolism which is similar in regard to AD concerning Aβ(1-42), but differs concerning sAPPα and -β. These results clearly indicate different pathologic pathways in AD and infectious CNS disease and may provide help in the differential biomarker diagnostics. Increased p-tau in HSV-1 encephalitis probably reflect acute neuronal damage and necrosis. PMID:23052602

  20. Hyperactivated Stat3 boosts axon regeneration in the CNS.

    PubMed

    Mehta, Saloni T; Luo, Xueting; Park, Kevin K; Bixby, John L; Lemmon, Vance P

    2016-06-01

    Axonal regeneration after spinal cord injury (SCI) is intrinsically and extrinsically inhibited by multiple factors. One major factor contributing to intrinsic regeneration failure is the inability of mature neurons in the central nervous system (CNS) to activate regeneration-associated transcription factors (TFs) post-injury. A prior study identified TFs overexpressed in neurons of the peripheral nervous system (PNS) compared to the CNS; some of these could be involved in the ability of PNS neurons to regenerate. Of these, signal transducer and activator of transcription 3 (STAT3), as well its downstream regeneration-associated targets, showed a significant upregulation in PNS neurons relative to CNS neurons, and a constitutively active variant of Stat3 (Stat3CA) promoted neurite growth when expressed in cerebellar neurons (Lerch et al., 2012; Smith et al., 2011). To further enhance STAT3's neurite outgrowth enhancing activity, Stat3CA was fused with a viral activation domain (VP16). VP16 hyperactivates TFs by recruiting transcriptional co-factors to the DNA binding domain (Hirai et al., 2010). Overexpression of this VP16-Stat3CA chimera in primary cortical neurons led to a significant increase of neurite outgrowth as well as Stat3 transcriptional activity in vitro. Furthermore, in vivo transduction of retinal ganglion cells (RGCs) with AAV constructs expressing VP16-Stat3CA resulted in regeneration of optic nerve axons after injury, to a greater degree than for those expressing Stat3CA alone. These findings confirm and extend the concept that overexpression of hyperactivated transcription factors identified as functioning in PNS regeneration can promote axon regeneration in the CNS. PMID:27060489

  1. Hyperbaric oxygen preconditioning protects rats against CNS oxygen toxicity.

    PubMed

    Arieli, Yehuda; Kotler, Doron; Eynan, Mirit; Hochman, Ayala

    2014-06-15

    We examined the hypothesis that repeated exposure to non-convulsive hyperbaric oxygen (HBO) as preconditioning provides protection against central nervous system oxygen toxicity (CNS-OT). Four groups of rats were used in the study. Rats in the control and the negative control (Ctl-) groups were kept in normobaric air. Two groups of rats were preconditioned to non-convulsive HBO at 202 kPa for 1h once every other day for a total of three sessions. Twenty-four hours after preconditioning, one of the preconditioned groups and the control rats were exposed to convulsive HBO at 608 kPa, and latency to CNS-OT was measured. Ctl- rats and the second preconditioned group (PrC-) were not subjected to convulsive HBO exposure. Tissues harvested from the hippocampus and frontal cortex were evaluated for enzymatic activity and nitrotyrosine levels. In the group exposed to convulsive oxygen at 608 kPa, latency to CNS-OT increased from 12.8 to 22.4 min following preconditioning. A significant decrease in the activity of glutathione reductase and glucose-6-phosphate dehydrogenase, and a significant increase in glutathione peroxidase activity, was observed in the hippocampus of preconditioned rats. Nitrotyrosine levels were significantly lower in the preconditioned animals, the highest level being observed in the control rats. In the cortex of the preconditioned rats, a significant increase was observed in glutathione S-transferase and glutathione peroxidase activity. Repeated exposure to non-convulsive HBO provides protection against CNS-OT. The protective mechanism involves alterations in the enzymatic activity of the antioxidant system and lower levels of peroxynitrite, mainly in the hippocampus. PMID:24675062

  2. Nanotechnology for CNS Delivery of Bio-Therapeutic Agents

    PubMed Central

    Shah, Lipa; Yadav, Sunita; Amiji, Mansoor

    2013-01-01

    The current therapeutic strategies are not efficient in treating disorders related to the central nervous system (CNS) and have only shown partial alleviation of symptoms, as opposed to, disease modifying effects. With change in population demographics, the incidence of CNS disorders, especially neurodegenerative diseases, is expected to rise dramatically. Current treatment regimens are associated with severe side-effects, especially given that most of these are chronic therapies and involve elderly population. In this review, we highlight the challenges and opportunities in delivering newer and more effective bio-therapeutic agents for the treatment of CNS disorders. Bio-therapeutics like proteins, peptides, monoclonal antibodies, growth factors, and nucleic acids are thought to have a profound effect on halting the progression of neurodegenerative disorders and also provide a unique function of restoring damaged cells. We provide a review of the nano-sized formulation-based drug delivery systems and alternate modes of delivery, like the intranasal route, to carry bio-therapeutics effectively to the brain. PMID:23894728

  3. PPAR agonists as therapeutics for CNS trauma and neurological diseases

    PubMed Central

    Mandrekar-Colucci, Shweta; Sauerbeck, Andrew; Popovich, Phillip G.; McTigue, Dana M.

    2013-01-01

    Traumatic injury or disease of the spinal cord and brain elicits multiple cellular and biochemical reactions that together cause or are associated with neuropathology. Specifically, injury or disease elicits acute infiltration and activation of immune cells, death of neurons and glia, mitochondrial dysfunction, and the secretion of substrates that inhibit axon regeneration. In some diseases, inflammation is chronic or non-resolving. Ligands that target PPARs (peroxisome proliferator-activated receptors), a group of ligand-activated transcription factors, are promising therapeutics for neurologic disease and CNS injury because their activation affects many, if not all, of these interrelated pathologic mechanisms. PPAR activation can simultaneously weaken or reprogram the immune response, stimulate metabolic and mitochondrial function, promote axon growth and induce progenitor cells to differentiate into myelinating oligodendrocytes. PPAR activation has beneficial effects in many pre-clinical models of neurodegenerative diseases and CNS injury; however, the mechanisms through which PPARs exert these effects have yet to be fully elucidated. In this review we discuss current literature supporting the role of PPAR activation as a therapeutic target for treating traumatic injury and degenerative diseases of the CNS. PMID:24215544

  4. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage

    PubMed Central

    Crane, Genevieve M.; Powell, Helen; Kostadinov, Rumen; Rocafort, Patrick Tim; Rifkin, Dena E.; Burger, Peter C.; Ambinder, Richard F.; Swinnen, Lode J.; Borowitz, Michael J.; Duffield, Amy S.

    2015-01-01

    Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) data file. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011–2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted. PMID:26460822

  5. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage.

    PubMed

    Crane, Genevieve M; Powell, Helen; Kostadinov, Rumen; Rocafort, Patrick Tim; Rifkin, Dena E; Burger, Peter C; Ambinder, Richard F; Swinnen, Lode J; Borowitz, Michael J; Duffield, Amy S

    2015-10-20

    Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) datafile. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011-2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted. PMID:26460822

  6. Nanotechnology for CNS delivery of bio-therapeutic agents.

    PubMed

    Shah, Lipa; Yadav, Sunita; Amiji, Mansoor

    2013-08-01

    The current therapeutic strategies are not efficient in treating disorders related to the central nervous system (CNS) and have only shown partial alleviation of symptoms, as opposed to, disease modifying effects. With change in population demographics, the incidence of CNS disorders, especially neurodegenerative diseases, is expected to rise dramatically. Current treatment regimens are associated with severe side-effects, especially given that most of these are chronic therapies and involve elderly population. In this review, we highlight the challenges and opportunities in delivering newer and more effective bio-therapeutic agents for the treatment of CNS disorders. Bio-therapeutics like proteins, peptides, monoclonal antibodies, growth factors, and nucleic acids are thought to have a profound effect on halting the progression of neurodegenerative disorders and also provide a unique function of restoring damaged cells. We provide a review of the nano-sized formulation-based drug delivery systems and alternate modes of delivery, like the intranasal route, to carry bio-therapeutics effectively to the brain. PMID:23894728

  7. Origin, fate and dynamics of macrophages at CNS interfaces

    PubMed Central

    Goldmann, Tobias; Jordão, Marta Joana Costa; Wieghofer, Peter; Prutek, Fabiola; Hagemeyer, Nora; Frenzel, Kathrin; Staszewski, Ori; Kierdorf, Katrin; Amann, Lukas; Krueger, Martin; Locatelli, Giuseppe; Hochgarner, Hannah; Zeiser, Robert; Epelman, Slava; Geissmann, Frederic; Priller, Josef; Rossi, Fabio; Bechmann, Ingo; Kerschensteiner, Martin; Linnarsson, Sten; Jung, Steffen; Prinz, Marco

    2016-01-01

    Perivascular, meningeal and choroid plexus macrophages are non-parenchymal macrophages that mediate immune responses at brain boundaries. Although the origin of parenchymal microglia has recently been elucidated, much less is known about the precursors, the underlying transcriptional program and the dynamics of the other macrophages in the central nervous system (CNS). It has been assumed that they have a high turnover with blood-borne monocytes. However, large scale single-cell RNA-sequencing reveals a striking molecular overlap between perivascular macrophages and microglia but not monocytes. Using several fate mapping approaches and parabiosis we demonstrate that CNS macrophages arise from yolk sac precursors during embryonic development and remain a stable population. Notably, the generation of CNS macrophages relies on the transcription factor Pu.1 whereas myb, Batf3 and Nr4a1 are not required. Upon autoimmune inflammation, macrophages undergo extensive self-renewal by local proliferation. Our data provide challenging new insights into brains innate immune system. PMID:27135602

  8. Microtubule-Targeting Agents Enter the Central Nervous System (CNS): Double-edged Swords for Treating CNS Injury and Disease

    PubMed Central

    2014-01-01

    Microtubules have been among the most successful targets in anticancer therapy and a large number of microtubule-targeting agents (MTAs) are in various stages of clinical development for the treatment of several malignancies. Given that injury and diseases in the central nervous system (CNS) are accompanied by acute or chronic disruption of the structural integrity of neurons and that microtubules provide structural support for the nervous system at cellular and intracellular levels, microtubules are emerging as potential therapeutic targets for treating CNS disorders. It has been postulated that exogenous application of MTAs might prevent the breakdown or degradation of microtubules after injury or during neurodegeneration, which will thereby aid in preserving the structural integrity and function of the nervous system. Here we review recent evidence that supports this notion and also discuss potential risks of targeting microtubules as a therapy for treating nerve injury and neurodegenerative diseases. PMID:25558415

  9. Methods for Gene Transfer to the Central Nervous System

    PubMed Central

    Kantor, Boris; Bailey, Rachel M.; Wimberly, Keon; Kalburgi, Sahana N.; Gray, Steven J.

    2015-01-01

    Gene transfer is an increasingly utilized approach for research and clinical applications involving the central nervous system (CNS). Vectors for gene transfer can be as simple as an unmodified plasmid, but more commonly involve complex modifications to viruses to make them suitable gene delivery vehicles. This chapter will explain how tools for CNS gene transfer have been derived from naturally occurring viruses. The current capabilities of plasmid, retroviral, adeno-associated virus, adenovirus, and herpes simplex virus vectors for CNS gene delivery will be described. These include both focal and global CNS gene transfer strategies, with short- or long-term gene expression. As is described in this chapter, an important aspect of any vector is the cis-acting regulatory elements incorporated into the vector genome that control when, where, and how the transgene is expressed. PMID:25311922

  10. WWOX At The Crossroads Of Cancer, Metabolic Syndrome Related Traits And CNS Pathologies

    PubMed Central

    Aldaz, C. Marcelo; Ferguson, Brent W.; Abba, Martin C.

    2014-01-01

    germline loss of function WWOX mutations have been identified. These patients are characterized by severe CNS related pathology that includes epilepsy, ataxia and mental retardation. In summary, WWOX is a highly conserved and tightly regulated gene throughout evolution and when defective or deregulated the consequences are important and deleterious as demonstrated by its association not only with poor prognosis in cancer but also with other important human pathologies such as metabolic syndrome and CNS related pathologic conditions. PMID:24932569

  11. A Synaptotagmin Isoform Switch during the Development of an Identified CNS Synapse.

    PubMed

    Kochubey, Olexiy; Babai, Norbert; Schneggenburger, Ralf

    2016-06-01

    Various Synaptotagmin (Syt) isoform genes are found in mammals, but it is unknown whether Syts can function redundantly in a given nerve terminal, or whether isoforms can be switched during the development of a nerve terminal. Here, we investigated the possibility of a developmental Syt isoform switch using the calyx of Held as a model synapse. At mature calyx synapses, fast Ca(2+)-driven transmitter release depended entirely on Syt2, but the release phenotype of Syt2 knockout (KO) mice was weaker at immature calyces, and absent at pre-calyceal synapses early postnatally. Instead, conditional genetic inactivation shows that Syt1 mediates fast release at pre-calyceal synapses, as well as a fast release component resistant to Syt2 deletion in immature calyces. This demonstrates a developmental Syt1-Syt2 isoform switch at an identified synapse, a mechanism that could fine-tune the speed, reliability, and plasticity of transmitter release at fast releasing CNS synapses. PMID:27210552

  12. Investigating CNS synaptogenesis at single-synapse resolution by combining reverse genetics with correlative light and electron microscopy.

    PubMed

    Urwyler, Olivier; Izadifar, Azadeh; Dascenco, Dan; Petrovic, Milan; He, Haihuai; Ayaz, Derya; Kremer, Anna; Lippens, Saskia; Baatsen, Pieter; Guérin, Christopher J; Schmucker, Dietmar

    2015-01-15

    Determining direct synaptic connections of specific neurons in the central nervous system (CNS) is a major technical challenge in neuroscience. As a corollary, molecular pathways controlling developmental synaptogenesis in vivo remain difficult to address. Here, we present genetic tools for efficient and versatile labeling of organelles, cytoskeletal components and proteins at single-neuron and single-synapse resolution in Drosophila mechanosensory (ms) neurons. We extended the imaging analysis to the ultrastructural level by developing a protocol for correlative light and 3D electron microscopy (3D CLEM). We show that in ms neurons, synaptic puncta revealed by genetically encoded markers serve as a reliable indicator of individual active zones. Block-face scanning electron microscopy analysis of ms axons revealed T-bar-shaped dense bodies and other characteristic ultrastructural features of CNS synapses. For a mechanistic analysis, we directly combined the single-neuron labeling approach with cell-specific gene disruption techniques. In proof-of-principle experiments we found evidence for a highly similar requirement for the scaffolding molecule Liprin-α and its interactors Lar and DSyd-1 (RhoGAP100F) in synaptic vesicle recruitment. This suggests that these important synapse regulators might serve a shared role at presynaptic sites within the CNS. In principle, our CLEM approach is broadly applicable to the developmental and ultrastructural analysis of any cell type that can be targeted with genetically encoded markers. PMID:25503410

  13. Processed pseudogenes acquired somatically during cancer development.

    PubMed

    Cooke, Susanna L; Shlien, Adam; Marshall, John; Pipinikas, Christodoulos P; Martincorena, Inigo; Tubio, Jose M C; Li, Yilong; Menzies, Andrew; Mudie, Laura; Ramakrishna, Manasa; Yates, Lucy; Davies, Helen; Bolli, Niccolo; Bignell, Graham R; Tarpey, Patrick S; Behjati, Sam; Nik-Zainal, Serena; Papaemmanuil, Elli; Teixeira, Vitor H; Raine, Keiran; O'Meara, Sarah; Dodoran, Maryam S; Teague, Jon W; Butler, Adam P; Iacobuzio-Donahue, Christine; Santarius, Thomas; Grundy, Richard G; Malkin, David; Greaves, Mel; Munshi, Nikhil; Flanagan, Adrienne M; Bowtell, David; Martin, Sancha; Larsimont, Denis; Reis-Filho, Jorge S; Boussioutas, Alex; Taylor, Jack A; Hayes, Neil D; Janes, Sam M; Futreal, P Andrew; Stratton, Michael R; McDermott, Ultan; Campbell, Peter J

    2014-01-01

    Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context. PMID:24714652

  14. Processed pseudogenes acquired somatically during cancer development

    PubMed Central

    Cooke, Susanna L.; Shlien, Adam; Marshall, John; Pipinikas, Christodoulos P.; Martincorena, Inigo; Tubio, Jose M.C.; Li, Yilong; Menzies, Andrew; Mudie, Laura; Ramakrishna, Manasa; Yates, Lucy; Davies, Helen; Bolli, Niccolo; Bignell, Graham R.; Tarpey, Patrick S.; Behjati, Sam; Nik-Zainal, Serena; Papaemmanuil, Elli; Teixeira, Vitor H.; Raine, Keiran; O’Meara, Sarah; Dodoran, Maryam S.; Teague, Jon W.; Butler, Adam P.; Iacobuzio-Donahue, Christine; Santarius, Thomas; Grundy, Richard G.; Malkin, David; Greaves, Mel; Munshi, Nikhil; Flanagan, Adrienne M.; Bowtell, David; Martin, Sancha; Larsimont, Denis; Reis-Filho, Jorge S.; Boussioutas, Alex; Taylor, Jack A.; Hayes, Neil D.; Janes, Sam M.; Futreal, P. Andrew; Stratton, Michael R.; McDermott, Ultan; Campbell, Peter J.; Provenzano, Elena; van de Vijver, Marc; Richardson, Andrea L.; Purdie, Colin; Pinder, Sarah; Mac Grogan, Gaetan; Vincent-Salomon, Anne; Larsimont, Denis; Grabau, Dorthe; Sauer, Torill; Garred, Øystein; Ehinger, Anna; Van den Eynden, Gert G.; van Deurzen, C.H.M; Salgado, Roberto; Brock, Jane E.; Lakhani, Sunil R.; Giri, Dilip D.; Arnould, Laurent; Jacquemier, Jocelyne; Treilleux, Isabelle; Caldas, Carlos; Chin, Suet-Feung; Fatima, Aquila; Thompson, Alastair M.; Stenhouse, Alasdair; Foekens, John; Martens, John; Sieuwerts, Anieta; Brinkman, Arjen; Stunnenberg, Henk; Span, Paul N.; Sweep, Fred; Desmedt, Christine; Sotiriou, Christos; Thomas, Gilles; Broeks, Annegein; Langerod, Anita; Aparicio, Samuel; Simpson, Peter T.; van ’t Veer, Laura; Erla Eyfjörd, Jórunn; Hilmarsdottir, Holmfridur; Jonasson, Jon G.; Børresen-Dale, Anne-Lise; Lee, Ming Ta Michael; Wong, Bernice Huimin; Tan, Benita Kiat Tee; Hooijer, Gerrit K.J.

    2014-01-01

    Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5′ truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context. PMID:24714652

  15. Role of ERK1/2 MAPK Signaling in the Maintenance of Myelin and Axonal Integrity in the Adult CNS

    PubMed Central

    Ishii, Akihiro; Furusho, Miki; Dupree, Jeffrey L.

    2014-01-01

    Oligodendrocytes form myelin during postnatal development and then maintain a functional myelin sheath throughout adult life. While many regulators of developmental myelination have been identified, the signal transduction mechanisms that regulate oligodendrocyte functions in adulthood are not well understood. The extracellular signal-regulated kinases-1 and -2 (ERK1/2), downstream mediators of mitogen-activated protein kinases (MAPKs), have emerged as prominent regulators of myelin formation. Here, we investigated whether these signaling molecules are also required for myelin maintenance in the adult CNS. Inducible conditional ablation of Erk1/2 in oligodendrocytes of the adult CNS resulted in a downregulation of myelin gene expression. Although myelin thickness was reduced and some axons were demyelinated, the majority of axons were wrapped by intact myelin sheaths that appeared structurally normal. However, late onset of progressive axonal degeneration, accompanied by astrogliosis, microglial activation, partial loss of oligodendrocytes, and functional impairment, occurred in the adult mice lacking ERK1/2 activity. Conditional ablation of Fibroblast Growth Factor receptors-1 and -2 (FGFR1/2) in oligodendrocytes also resulted in downregulation of myelin gene expression and development of axonal degeneration as the mice aged. Further, the level of the key transcription factor myelin gene regulatory factor (Myrf) was downregulated or upregulated in mice with genetic loss or gain of ERK1/2 function, respectively. Together, our studies demonstrate that ERK1/2-MAPK signaling is required for the long-term maintenance of myelin and axonal integrity in the adult CNS and suggest that FGFR1/2 and Myrf may, in part, contribute to signaling upstream and downstream of ERK1/2 in maintaining these oligodendrocyte functions during adulthood. PMID:25429144

  16. Role of ERK1/2 MAPK signaling in the maintenance of myelin and axonal integrity in the adult CNS.

    PubMed

    Ishii, Akihiro; Furusho, Miki; Dupree, Jeffrey L; Bansal, Rashmi

    2014-11-26

    Oligodendrocytes form myelin during postnatal development and then maintain a functional myelin sheath throughout adult life. While many regulators of developmental myelination have been identified, the signal transduction mechanisms that regulate oligodendrocyte functions in adulthood are not well understood. The extracellular signal-regulated kinases-1 and -2 (ERK1/2), downstream mediators of mitogen-activated protein kinases (MAPKs), have emerged as prominent regulators of myelin formation. Here, we investigated whether these signaling molecules are also required for myelin maintenance in the adult CNS. Inducible conditional ablation of Erk1/2 in oligodendrocytes of the adult CNS resulted in a downregulation of myelin gene expression. Although myelin thickness was reduced and some axons were demyelinated, the majority of axons were wrapped by intact myelin sheaths that appeared structurally normal. However, late onset of progressive axonal degeneration, accompanied by astrogliosis, microglial activation, partial loss of oligodendrocytes, and functional impairment, occurred in the adult mice lacking ERK1/2 activity. Conditional ablation of Fibroblast Growth Factor receptors-1 and -2 (FGFR1/2) in oligodendrocytes also resulted in downregulation of myelin gene expression and development of axonal degeneration as the mice aged. Further, the level of the key transcription factor myelin gene regulatory factor (Myrf) was downregulated or upregulated in mice with genetic loss or gain of ERK1/2 function, respectively. Together, our studies demonstrate that ERK1/2-MAPK signaling is required for the long-term maintenance of myelin and axonal integrity in the adult CNS and suggest that FGFR1/2 and Myrf may, in part, contribute to signaling upstream and downstream of ERK1/2 in maintaining these oligodendrocyte functions during adulthood. PMID:25429144

  17. AUTOLOGOUS HAEMATOPOIETIC CELL TRANSPLANTATION FOR NON-HODGKIN LYMPHOMA WITH SECONDARY CNS INVOLVEMENT

    PubMed Central

    Maziarz, Richard T.; Wang, Zhiwei; Zhang, Mei-Jie; Bolwell, Brian J.; Chen, Andy I.; Fenske, Timothy S.; Freytes, Cesar O.; Gale, Robert Peter; Gibson, John; Hayes-Lattin, Brandon M.; Holmberg, Leona; Inwards, David J.; Isola, Luis M.; Khoury, H. Jean; Lewis, Victor A.; Maharaj, Dipnarine; Munker, Reinhold; Phillips, Gordon L.; Rizzieri, David A.; Rowlings, Philip A.; Saber, Wael; Satwani, Prakash; Waller, Edmund K.; Maloney, David G.; Montoto, Silvia; Laport, Ginna G.; Vose, Julie M.; Lazarus, Hillard M.; Hari, Parameswaran N.

    2013-01-01

    SUMMARY Pre-existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non-Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS+) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS−). There were significant baseline differences between the cohorts. CNS+ patients were more likely to be younger, have lower performance scores, higher age-adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression-free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS+ group with a subset of CNS− patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n=55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n=96) at the time of AHCT. CNS+ patients can achieve excellent long-term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis. PMID:23829536

  18. New perspectives on using brain imaging to study CNS stimulants.

    PubMed

    Lukas, Scott E

    2014-12-01

    While the recent application of brain imaging to study CNS stimulants has offered new insights into the fundamental factors that contribute to their use and abuse, many gaps remain. Brain circuits that mediate pleasure, dependence, craving and relapse are anatomically, neurophysiologically and neurochemically distinct from one another, which has guided the search for correlates of stimulant-seeking and taking behavior. However, unlike other drugs of abuse, metrics for tolerance and physical dependence on stimulants are not obvious. The dopamine theory of stimulant abuse does not sufficiently explain this disorder as serotonergic, GABAergic and glutamagergic circuits are clearly involved in stimulant pharmacology and so tracking the source of the "addictive" processes must adopt a more multimodal, multidisciplinary approach. To this end, both anatomical and functional magnetic resonance imaging (MRI), MR spectroscopy (MRS) and positron emission tomography (PET) are complementary and have equally contributed to our understanding of how stimulants affect the brain and behavior. New vistas in this area include nanotechnology approaches to deliver small molecules to receptors and use MRI to resolve receptor dynamics. Anatomical and blood flow imaging has yielded data showing that cognitive enhancers might be useful adjuncts in treating CNS stimulant dependence, while MRS has opened opportunities to examine the brain's readiness to accept treatment as GABA tone normalizes after detoxification. A desired outcome of the above approaches is being able to offer evidence-based rationales for treatment approaches that can be implemented in a more broad geographic area, where access to brain imaging facilities may be limited. This article is part of the Special Issue entitled 'CNS Stimulants'. PMID:25080072

  19. CNS intraoperative consultation: a survival guide for non-neuropathologists.

    PubMed

    Kresak, Jesse Lee; Rivera-Zengotita, Marie; Foss, Robin M; Yachnis, Anthony T

    2014-01-01

    Intraoperative consultations for central nervous system disease may be challenging due to limitations of sample size, lack of familiarity with neurosurgical procedures, or poor access to neuroimaging studies. Despite these challenges, the surgical pathologist is charged with determining if the tissue sample is representative of the pathologic process while ensuring that enough diagnostic tissue has been retained for routine histology, immunohistochemistry, fluorescence in situ hybridization, molecular testing, and in some cases, tissue banking. Here, we present basic methods and a practical approach for CNS intraoperative consultation including critical pre-analytic considerations that promote optimal tissue management. PMID:25015160

  20. Kynurenines in CNS disease: regulation by inflammatory cytokines.

    PubMed

    Campbell, Brian M; Charych, Erik; Lee, Anna W; Möller, Thomas

    2014-01-01

    The kynurenine pathway (KP) metabolizes the essential amino acid tryptophan and generates a number of neuroactive metabolites collectively called the kynurenines. Segregated into at least two distinct branches, often termed the "neurotoxic" and "neuroprotective" arms of the KP, they are regulated by the two enzymes kynurenine 3-monooxygenase and kynurenine aminotransferase, respectively. Interestingly, several enzymes in the pathway are under tight control of inflammatory mediators. Recent years have seen a tremendous increase in our understanding of neuroinflammation in CNS disease. This review will focus on the regulation of the KP by inflammatory mediators as it pertains to neurodegenerative and psychiatric disorders. PMID:24567701

  1. CNS depressant activities of roots of Coccos nucifera in mice.

    PubMed

    Pal, Dilipkumar; Sarkar, Abhijit; Gain, Sumanta; Jana, Sandip; Mandal, Soumit

    2011-01-01

    The ethanol extract of Coccos nucifera (EECN) was tested for possible pharmacological effects on experimental animals. EECN significantly potentiated the sleeping time of mice induced by standard hypnotics viz. pentobarbital sodium, diazepam, and meprobamate in a dose dependent manner. EECN showed significant analgesic properties as evidenced by the significant reduction in the number of writhes and stretches induced in mice by 1.2% acetic acid solution. It also potentiated analgesia induced by morphine and pethidine in mice. Pretreatment with EECN caused significant protection against pentylenetetrazole-induced convulsions. The behavioral studies on mice indicate CNS depressant activity of the ethanol extract of C. nucifera. PMID:21485298

  2. Aluminum, the genetic apparatus of the human CNS and Alzheimer's disease (AD).

    PubMed

    Pogue, A I; Lukiw, W J

    2016-06-01

    The genomes of eukaryotes orchestrate their expression to ensure an effective, homeostatic and functional gene signaling program, and this includes fundamentally altered patterns of transcription during aging, development, differentiation and disease. These actions constitute an extremely complex and intricate process as genetic operations such as transcription involve the very rapid translocation and polymerization of ribonucleotides using RNA polymerases, accessory transcription protein complexes and other interrelated chromatin proteins and genetic factors. As both free ribonucleotides and polymerized single-stranded RNA chains, ribonucleotides are highly charged with phosphate, and this genetic system is extremely vulnerable to disruption by a large number of electrostatic forces, and primarily by cationic metals such as aluminum. Aluminum has been shown by independent researchers to be particularly genotoxic to the genetic apparatus, and it has become reasonably clear that aluminum disturbs genetic signaling programs in the CNS that bear a surprising resemblance to those observed in Alzheimer's disease (AD) brain. This paper will focus on a discussion of two molecular-genetic aspects of aluminum genotoxicity: (1) the observation that micro-RNA (miRNA)-mediated global gene expression patterns in aluminum-treated transgenic animal models of AD (Tg-AD) strongly resemble those found in AD; and (2) the concept of "human biochemical individuality" and the hypothesis that individuals with certain gene expression patterns may be especially sensitive and perhaps predisposed to aluminum genotoxicity. PMID:26969391

  3. Detection of stapylococcal enterotoxin, methicillin-resistant and Panton-Valentine leukocidin genes in coagulase-negative staphylococci isolated from cows and ewes with subclinical mastitis.

    PubMed

    Unal, Nilgün; Cinar, Oya Doğu

    2012-02-01

    Coagulase-negative staphylococci (CNS) are the most prevalent mastitis pathogens. However, virulence characteristics of CNS have not been well determined. The presence of genes for enterotoxins (sea-sej), toxic shock syndrome toxin-1 (tst), the exfoliative toxins (eta, etb), Panton-Valentine leukocidin (pvl) and mecA of CNS species isolated from cows and ewes with subclinical mastitis was investigated in this study. A total of 121 CNS (81 cows, 40 ewes) representing 18 different Staphylococci species were examined by PCR, and 38.1% (33 cows and 13 ewes) of CNS isolates had one or more se genes. The difference between percentages for SE toxin genes of CNS strains isolated from cows (40.7%) and ewes (32.5%) was not statistically significant (P > 0.05; χ(2) = 0.380). It was found that S. simulans isolates had the highest prevalent se genes. Furthermore, the most common SE gene types was seh-sej. In this study, none of the isolates harbored the toxic shock syndrome toxin gene (tsst) and the exfoliative toxin genes (eta, etb). Five cow (6.17%) and three ewe CNS (7.5%) isolates had mecA gene. Three cow (3.7%) and two ewe CNS (5.0%) isolates had pvl gene. In conclusion, the present study showed that CNS species isolated from cows and ewes could serve as potential reservoir of se, mecA, and pvl genes. PMID:22160510

  4. Acquired Equivalence Changes Stimulus Representations

    ERIC Educational Resources Information Center

    Meeter, M.; Shohamy, D.; Myers, C. E.

    2009-01-01

    Acquired equivalence is a paradigm in which generalization is increased between two superficially dissimilar stimuli (or antecedents) that have previously been associated with similar outcomes (or consequents). Several possible mechanisms have been proposed, including changes in stimulus representations, either in the form of added associations or…

  5. Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders

    PubMed Central

    Schadt, Eric E.; Buchanan, Sean; Brennand, Kristen J.; Merchant, Kalpana M.

    2014-01-01

    A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer’s Disease, and the psychiatric disorder schizophrenia, we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to construct

  6. Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders.

    PubMed

    Schadt, Eric E; Buchanan, Sean; Brennand, Kristen J; Merchant, Kalpana M

    2014-01-01

    A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer's Disease, and the psychiatric disorder schizophrenia, we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to construct

  7. CNS stimulants and the look-alike drugs.

    PubMed

    Lake, C R; Quirk, R S

    1984-12-01

    Abuse of amphetamine and especially the stimulant look-alikes represent a serious problem in the United States. The danger of amphetamine lies in its ability to produce tolerance, psychological addiction, psychosis, hypertensive crisis, and major depression following withdrawal after long-term use. The danger of the look-alikes is of a psychosocial nature and has less to do with the physical properties of the drugs. Easy availability and a casual attitude toward these drugs may introduce children and young adults to the concept of recreational use of drugs at an early age. Look-alikes also divert the efforts of law enforcement officials whose time is better spent on efforts to control illegal distribution of controlled substances. However, look-alikes do produce severe to life-threatening effects including seizures, hypertensive crises, and psychoses. Unfortunately, there are no fast and easy solutions to the stimulant drug abuse problem. Abuse of CNS stimulants has a long history. Effective approaches must involve greater education about the dangers of these drugs and improved recognition among medical professionals of trends in CNS stimulant abuse in order to better diagnose and treat resulting problems. It is unlikely that federal controls on amphetamine production can be increased. The OTC drugs, such as PPA, caffeine, and ephedrine could be moved to prescription-only status to emphasize their potential for abuse and for producing adverse reactions, but this approach is counter to society's current trend toward self-medication. PMID:6151645

  8. Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

    PubMed Central

    Upadhyay, Ravi Kant

    2014-01-01

    Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB) for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods. PMID:25136634

  9. CNS effects of sumatriptan and rizatriptan in healthy female volunteers.

    PubMed

    van der Post, J; Schram, M T; Schoemaker, R C; Pieters, M S M; Fuseau, E; Pereira, A; Baggen, S; Cohen, A F; van Gerven, J M A

    2002-05-01

    This study investigates the CNS effects of sumatriptan and rizatriptan, with temazepam as an active comparator, in healthy female volunteers. Sixteen volunteers completed a randomized, double-blind, crossover study and on four separate occasions received either 100 mg sumatriptan, 20 mg rizatriptan or 20 mg temazepam. The main parameters were eye movements, EEG, body sway, visual analogue scales and a cognitive test battery. Rizatriptan and sumatriptan decreased saccadic peak velocity by 18.3 (95% CI: 5.7, 30.8) and 15.0 (2.2, 27.9) degrees/sec, respectively, about half the decrease induced by temazepam (35.0 (22.1, 47.8) degrees/sec). Body sway increased (30% for rizatriptan (16%, 45%) and 14% for sumatriptan (1%, 27%), respectively). Temazepam caused larger, similar effects. In contrast to temazepam, sumatriptan and rizatriptan decreased reaction times of recognition tasks and increased EEG alpha power (significant for sumatriptan, 0.477 (0.02, 0.935). Therapeutic doses of sumatriptan and rizatriptan caused CNS effects indicative of mild sedation. For EEG and recognition reaction times the effects were opposite to temazepam, indicating central stimulation. PMID:12100089

  10. MicroRNAs as biomarkers for CNS disease

    PubMed Central

    Rao, Pooja; Benito, Eva; Fischer, André

    2013-01-01

    For many neurological diseases, the efficacy and outcome of treatment depend on early detection. Diagnosis is currently based on the detection of symptoms and neuroimaging abnormalities, which appear at relatively late stages in the pathogenesis. However, the underlying molecular responses to genetic and environmental insults begin much earlier and non-coding RNA networks are critically involved in these cellular regulatory mechanisms. Profiling RNA expression patterns could thus facilitate presymptomatic disease detection. Obtaining indirect readouts of pathological processes is particularly important for brain disorders because of the lack of direct access to tissue for molecular analyses. Living neurons and other CNS cells secrete microRNA and other small non-coding RNA into the extracellular space packaged in exosomes, microvesicles, or lipoprotein complexes. This discovery, together with the rapidly evolving massive sequencing technologies that allow detection of virtually all RNA species from small amounts of biological material, has allowed significant progress in the use of extracellular RNA as a biomarker for CNS malignancies, neurological, and psychiatric diseases. There is also recent evidence that the interactions between external stimuli and brain pathological processes may be reflected in peripheral tissues, facilitating their use as potential diagnostic markers. In this review, we explore the possibilities and challenges of using microRNA and other small RNAs as a signature for neurodegenerative and other neuropsychatric conditions. PMID:24324397

  11. Oligodendrocyte death results in immune-mediated CNS demyelination

    PubMed Central

    Traka, Maria; Podojil, Joseph R; McCarthy, Derrick P; Miller, Stephen D; Popko, Brian

    2016-01-01

    Although multiple sclerosis is a common neurological disorder, the origin of the autoimmune response against myelin, which is the characteristic feature of the disease, remains unclear. To investigate whether oligodendrocyte death could cause this autoimmune response, we examined the oligodendrocyte ablation Plp1-CreERT;ROSA26-eGFP-DTA (DTA) mouse model. Approximately 30 weeks after recovering from oligodendrocyte loss and demyelination, DTA mice develop a fatal secondary disease characterized by extensive myelin and axonal loss. Strikingly, late-onset disease was associated with increased numbers of T lymphocytes in the CNS and myelin oligodendrocyte glycoprotein (MOG)-specific T cells in lymphoid organs. Transfer of T cells derived from DTA mice to naive recipients resulted in neurological defects that correlated with CNS white matter inflammation. Furthermore, immune tolerization against MOG ameliorated symptoms. Overall, these data indicate that oligodendrocyte death is sufficient to trigger an adaptive autoimmune response against myelin, suggesting that a similar process can occur in the pathogenesis of multiple sclerosis. PMID:26656646

  12. Nicotinic ACh receptors as therapeutic targets in CNS disorders.

    PubMed

    Dineley, Kelly T; Pandya, Anshul A; Yakel, Jerrel L

    2015-02-01

    The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor (nAChR) channels. These receptors are widely distributed throughout the central nervous system (CNS), being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however, the α7 and α4β2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer's disease, AD), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain. PMID:25639674

  13. Distinct roles of T-cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity.

    PubMed

    Fischer, Henrike J; Witte, Ann-Kathrin; Walter, Lutz; Gröne, Hermann-Josef; van den Brandt, Jens; Reichardt, Holger M

    2016-05-01

    T-cell lymphopenia is a major risk factor for autoimmunity. Here we describe congenic Lewis (LEW) rats with a loss-of-function mutation in the Gimap5 gene, leading to a 92% reduction in peripheral T-cell numbers. Gimap5-deficient LEW rats developed eosinophilic autoimmune gastroenteritis accompanied by a 40-fold increase in IgE serum levels. This phenotype was ameliorated by antibiotic treatment, indicating a critical role of the microbial flora in the development of inflammatory bowel disease. Interestingly, Gimap5-deficient LEW rats showed strongly aggravated experimental autoimmune encephalomyelitis (EAE) after immunization with guinea pig myelin basic protein. This phenotype, however, persisted after antibiosis, confirming that the enhanced CNS autoimmune response in T-cell lymphopenic Gimap5-deficient LEW rats was unrelated to the composition of the microbial flora. Rather, it seems that it was caused by the 7-fold increase in the percentage of activated T cells producing IL-17 and IFN-γ, and the skewed T-cell receptor (TCR) repertoire, both of which were the result of T-cell lymphopenia and not affected by antibiosis. This notion was supported by the observation that adoptive T-cell transfer corrected the TCR repertoire and improved EAE. Collectively, our findings confirm a critical albeit differential role of T-cell lymphopenia in the susceptibility to organ-specific autoimmune responses.-Fischer, H. J., Witte, A.-K., Walter, L., Gröne, H.-J., van den Brandt, J., Reichardt, H. M. Distinct roles of T-cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity. PMID:26740263

  14. Rescue of peripheral and CNS axon defects in mice lacking NMNAT2.

    PubMed

    Gilley, Jonathan; Adalbert, Robert; Yu, Gang; Coleman, Michael P

    2013-08-14

    NMNAT2 is an NAD(+)-synthesizing enzyme with an essential axon maintenance role in primary culture neurons. We have generated an Nmnat2 gene trap mouse to examine the role of NMNAT2 in vivo. Homozygotes die perinatally with a severe peripheral nerve/axon defect and truncated axons in the optic nerve and other CNS regions. The cause appears to be limited axon extension, rather than dying-back degeneration of existing axons, which was previously proposed for the NMNAT2-deficient Blad mutant mouse. Neurite outgrowth in both PNS and CNS neuronal cultures consistently stalls at 1-2 mm, similar to the length of truncated axons in the embryos. Crucially, this suggests an essential role for NMNAT2 during axon growth. In addition, we show that the Wallerian degeneration slow protein (Wld(S)), a more stable, aberrant NMNAT that can substitute the axon maintenance function of NMNAT2 in primary cultures, can also correct developmental defects associated with NMNAT2 deficiency. This is dose-dependent, with extension of life span to at least 3 months by homozygous levels of Wld(S) the most obvious manifestation. Finally, we propose that endogenous mechanisms also compensate for otherwise limiting levels of NMNAT2. This could explain our finding that conditional silencing of a single Nmnat2 allele triggers substantial degeneration of established neurites, whereas similar, or greater, reduction of NMNAT2 in constitutively depleted neurons is compatible with normal axon growth and survival. A requirement for NMNAT2 for both axon growth and maintenance suggests that reduced levels could impair axon regeneration as well as axon survival in aging and disease. PMID:23946398

  15. Overview of Transgenic Glioblastoma and Oligoastrocytoma CNS Models and Their Utility in Drug Discovery.

    PubMed

    Chen, Fuyi; Becker, Albert; LoTurco, Joseph

    2016-01-01

    Many animal models have been developed to investigate the sources of central nervous system (CNS) tumor heterogeneity. Reviewed in this unit is a recently developed CNS tumor model using the piggyBac transposon system delivered by in utero electroporation, in which sources of tumor heterogeneity can be conveniently studied. Their applications for studying CNS tumors and drug discovery are also reviewed. © 2016 by John Wiley & Sons, Inc. PMID:26995546

  16. Accepting Foreign Genes.

    PubMed

    Boto, Luis

    2016-05-01

    Three recent papers underline the importance of the host genomic background in allowing the stable maintenance of horizontally acquired genes. These studies suggest that post-transfer changes in both host genome and acquired genes contribute to the stable integration of foreign genes. PMID:27075565

  17. Potential DNA slippage structures acquired during evolutionary divergence of Acinetobacter calcoaceticus chromosomal benABC and Pseudomonas putida TOL pWW0 plasmid xylXYZ, genes encoding benzoate dioxygenases.

    PubMed Central

    Harayama, S; Rekik, M; Bairoch, A; Neidle, E L; Ornston, L N

    1991-01-01

    The xylXYZ DNA region is carried on the TOL pWW0 plasmid in Pseudomonas putida and encodes a benzoate dioxygenase with broad substrate specificity. The DNA sequence of the region is presented and compared with benABC, the chromosomal region encoding the benzoate dioxygenase of Acinetobacter calcoaceticus. Corresponding genes from the two biological sources share common ancestry: comparison of aligned XylX-BenA, XylY-BenB, and XylZ-BenC amino acid sequences revealed respective identities of 58.3, 61.3, and 53%. The aligned genes have diverged to assume G+C contents that differ by 14.0 to 14.9%. Usage of the unusual arginine codons AGA and AGG appears to have been selected in the P. putida xylX gene as it diverged from the ancestor it shared with A. calcoaceticus benA. Homologous A. calcoaceticus and P. putida genes exhibit different patterns of DNA sequence repetition, and analysis of one such pattern suggests that mutations creating different DNA slippage structures made a significant contribution to the evolutionary divergence of xylX. PMID:1938949

  18. Impact of lactobacilli on orally acquired listeriosis

    PubMed Central

    Archambaud, Cristel; Nahori, Marie-Anne; Soubigou, Guillaume; Bécavin, Christophe; Laval, Laure; Lechat, Pierre; Smokvina, Tamara; Langella, Philippe; Lecuit, Marc; Cossart, Pascale

    2012-01-01

    Listeria monocytogenes is a foodborne pathogen that crosses the intestinal barrier and disseminates within the host. Here, we report a unique comprehensive analysis of the impact of two Lactobacillus species, Lactobacillus paracasei CNCM I-3689 and Lactobacillus casei BL23, on L. monocytogenes and orally acquired listeriosis in a gnotobiotic humanized mouse model. We first assessed the effect of treatment with each Lactobacillus on L. monocytogenes counts in host tissues and showed that each decreases L. monocytogenes systemic dissemination in orally inoculated mice. A whole genome intestinal transcriptomic analysis revealed that each Lactobacillus changes expression of a specific subset of genes during infection, with IFN-stimulated genes (ISGs) being the most affected by both lactobacilli. We also examined microRNA (miR) expression and showed that three miRs (miR-192, miR-200b, and miR-215) are repressed during L. monocytogenes infection. Treatment with each Lactobacillus increased miR-192 expression, whereas only L. casei association increased miR-200b and miR-215 expression. Finally, we showed that treatment with each Lactobacillus significantly reshaped the L. monocytogenes transcriptome and up-regulated transcription of L. monocytogenes genes encoding enzymes allowing utilization of intestinal carbon and nitrogen sources in particular genes involved in propanediol and ethanolamine catabolism and cobalamin biosynthesis. Altogether, these data reveal that the modulation of L. monocytogenes infection by treatment with lactobacilli correlates with a decrease in host gene expression, in particular ISGs, miR regulation, and a dramatic reshaping of L. monocytogenes transcriptome. PMID:23012479

  19. Impact of lactobacilli on orally acquired listeriosis.

    PubMed

    Archambaud, Cristel; Nahori, Marie-Anne; Soubigou, Guillaume; Bécavin, Christophe; Laval, Laure; Lechat, Pierre; Smokvina, Tamara; Langella, Philippe; Lecuit, Marc; Cossart, Pascale

    2012-10-01

    Listeria monocytogenes is a foodborne pathogen that crosses the intestinal barrier and disseminates within the host. Here, we report a unique comprehensive analysis of the impact of two Lactobacillus species, Lactobacillus paracasei CNCM I-3689 and Lactobacillus casei BL23, on L. monocytogenes and orally acquired listeriosis in a gnotobiotic humanized mouse model. We first assessed the effect of treatment with each Lactobacillus on L. monocytogenes counts in host tissues and showed that each decreases L. monocytogenes systemic dissemination in orally inoculated mice. A whole genome intestinal transcriptomic analysis revealed that each Lactobacillus changes expression of a specific subset of genes during infection, with IFN-stimulated genes (ISGs) being the most affected by both lactobacilli. We also examined microRNA (miR) expression and showed that three miRs (miR-192, miR-200b, and miR-215) are repressed during L. monocytogenes infection. Treatment with each Lactobacillus increased miR-192 expression, whereas only L. casei association increased miR-200b and miR-215 expression. Finally, we showed that treatment with each Lactobacillus significantly reshaped the L. monocytogenes transcriptome and up-regulated transcription of L. monocytogenes genes encoding enzymes allowing utilization of intestinal carbon and nitrogen sources in particular genes involved in propanediol and ethanolamine catabolism and cobalamin biosynthesis. Altogether, these data reveal that the modulation of L. monocytogenes infection by treatment with lactobacilli correlates with a decrease in host gene expression, in particular ISGs, miR regulation, and a dramatic reshaping of L. monocytogenes transcriptome. PMID:23012479

  20. Acquired causes of intestinal malabsorption.

    PubMed

    van der Heide, F

    2016-04-01

    This review focuses on the acquired causes, diagnosis, and treatment of intestinal malabsorption. Intestinal absorption is a complex process that depends on many variables, including the digestion of nutrients within the intestinal lumen, the absorptive surface of the small intestine, the membrane transport systems, and the epithelial absorptive enzymes. Acquired causes of malabsorption are classified by focussing on the three phases of digestion and absorption: 1) luminal/digestive phase, 2) mucosal/absorptive phase, and 3) transport phase. Most acquired diseases affect the luminal/digestive phase. These include short bowel syndrome, extensive small bowel inflammation, motility disorders, and deficiencies of digestive enzymes or bile salts. Diagnosis depends on symptoms, physical examination, and blood and stool tests. There is no gold standard for the diagnosis of malabsorption. Further testing should be based on the specific clinical context and the suspected underlying disease. Therapy is directed at nutritional support by enteral or parenteral feeding and screening for and supplementation of deficiencies in vitamins and minerals. Early enteral feeding is important for intestinal adaptation in short bowel syndrome. Medicinal treatment options for diarrhoea in malabsorption include loperamide, codeine, cholestyramine, or antibiotics. PMID:27086886

  1. Definitive Identification of Laribacter hongkongensis Acquired in the United States

    PubMed Central

    Quig, David; Block, Mary Ann; Schreckenberger, Paul C.

    2015-01-01

    Laribacter hongkongensis is a potential emerging pathogen associated with community-acquired gastroenteritis and traveler's diarrhea. We report the isolation of L. hongkongensis from the stool of a patient who had no history of travel outside the United States. The organism was identified by phenotypic tests, mass spectrometry, and gene sequencing. PMID:25948608

  2. Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series

    PubMed Central

    Jaunmuktane, Zane; Sheerin, Una-Marie; Phadke, Rahul; Brandner, Sebastian; Milonas, Ionnis; Dean, Andrew; Bajaj, Nin; McNicholas, Nuala; Costello, Daniel; Cronin, Simon; McGuigan, Chris; Rossor, Martin; Fox, Nick; Murphy, Elaine; Chataway, Jeremy; Houlden, Henry

    2016-01-01

    Background Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. Methods In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. Results Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. Conclusion We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia. PMID:25935893

  3. Genetic and Biochemical Characterization of an Acquired Subgroup B3 Metallo-β-Lactamase Gene, blaAIM-1, and Its Unique Genetic Context in Pseudomonas aeruginosa from Australia

    PubMed Central

    Yong, Dongeun; Toleman, Mark A.; Bell, Jan; Ritchie, Brett; Pratt, Rachael; Ryley, Henry

    2012-01-01

    Three clinical Pseudomonas aeruginosa isolates (WCH2677, WCH2813, and WCH2837) isolated from the Women's and Children's Hospital, Adelaide, Australia, produced a metallo-β-lactamase (MBL)-positive Etest result. All isolates were PCR negative for known MBL genes. A gene bank was created, and an MBL gene, designated blaAIM-1, was cloned and fully characterized. The encoded enzyme, AIM-1, is a group B3 MBL that has the highest level of identity to THIN-B and L1. It is chromosomal and flanked by two copies (one intact and one truncated) of an ISCR element, ISCR15. Southern hybridization studies indicated the movement of both ISCR15 and blaAIM-1 within the three different clinical isolates. AIM-1 hydrolyzes most β-lactams, with the exception of aztreonam and, to a lesser extent, ceftazidime; however, it possesses significantly higher kcat values for cefepime and carbapenems than most other MBLs. AIM-1 was the first mobile group B3 enzyme detected and signals further problems for already beleaguered antimicrobial regimes to treat serious P. aeruginosa and other Gram-negative infections. PMID:22985886

  4. Genetic and biochemical characterization of an acquired subgroup B3 metallo-β-lactamase gene, blaAIM-1, and its unique genetic context in Pseudomonas aeruginosa from Australia.

    PubMed

    Yong, Dongeun; Toleman, Mark A; Bell, Jan; Ritchie, Brett; Pratt, Rachael; Ryley, Henry; Walsh, Timothy R

    2012-12-01

    Three clinical Pseudomonas aeruginosa isolates (WCH2677, WCH2813, and WCH2837) isolated from the Women's and Children's Hospital, Adelaide, Australia, produced a metallo-β-lactamase (MBL)-positive Etest result. All isolates were PCR negative for known MBL genes. A gene bank was created, and an MBL gene, designated bla(AIM-1), was cloned and fully characterized. The encoded enzyme, AIM-1, is a group B3 MBL that has the highest level of identity to THIN-B and L1. It is chromosomal and flanked by two copies (one intact and one truncated) of an ISCR element, ISCR15. Southern hybridization studies indicated the movement of both ISCR15 and bla(AIM-1) within the three different clinical isolates. AIM-1 hydrolyzes most β-lactams, with the exception of aztreonam and, to a lesser extent, ceftazidime; however, it possesses significantly higher k(cat) values for cefepime and carbapenems than most other MBLs. AIM-1 was the first mobile group B3 enzyme detected and signals further problems for already beleaguered antimicrobial regimes to treat serious P. aeruginosa and other Gram-negative infections. PMID:22985886

  5. Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence

    PubMed Central

    Abid, Muhammad Bilal; De Mel, Sanjay; Abid, Muhammad Abbas; Tan, Kong Bing; Chng, Wee Joo

    2016-01-01

    ABSTRACT Background: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. Case presentation: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. Discussion: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. Conclusion: In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration. PMID:27105248

  6. Autoimmune control of lesion growth in CNS with minimal damage

    NASA Astrophysics Data System (ADS)

    Mathankumar, R.; Mohan, T. R. Krishna

    2013-07-01

    Lesions in central nervous system (CNS) and their growth leads to debilitating diseases like Multiple Sclerosis (MS), Alzheimer's etc. We developed a model earlier [1, 2] which shows how the lesion growth can be arrested through a beneficial auto-immune mechanism. We compared some of the dynamical patterns in the model with different facets of MS. The success of the approach depends on a set of control parameters and their phase space was shown to have a smooth manifold separating the uncontrolled lesion growth region from the controlled. Here we show that an optimal set of parameter values exist in the model which minimizes system damage while, at once, achieving control of lesion growth.

  7. Preparation of embryonic retinal explants to study CNS neurite growth.

    PubMed

    Hanea, Sonia T; Shanmugalingam, Ushananthini; Fournier, Alyson E; Smith, Patrice D

    2016-05-01

    This protocol outlines the preparation of embryonic mouse retinal explants, which provides an effective technique to analyze neurite outgrowth in central nervous system (CNS) neurons. This validated ex vivo system, which displays limited neuronal death, is highly reproducible and particularly amenable to manipulation. Our previously published studies involving embryonic chick or adult mouse retinal explants were instrumental in the preparation of this protocol; aspects of these previous techniques were combined, adopted and optimized. This protocol thus permits more efficient analysis of neurite growth. Briefly, the retina is dissected from the embryonic mouse eye using precise techniques that take into account the small size of the embryonic eye. The approach applied ensures that the retinal ganglion cell (RGC) layer faces the adhesion substrate on coated cover slips. Neurite growth is clear, well-delineated and readily quantifiable. These retinal explants can therefore be used to examine the neurite growth effects elicited by potential therapeutic agents. PMID:27072342

  8. CNS myelin wrapping is driven by actin disassembly.

    PubMed

    Zuchero, J Bradley; Fu, Meng-Meng; Sloan, Steven A; Ibrahim, Adiljan; Olson, Andrew; Zaremba, Anita; Dugas, Jason C; Wienbar, Sophia; Caprariello, Andrew V; Kantor, Christopher; Leonoudakis, Dmitri; Leonoudakus, Dmitri; Lariosa-Willingham, Karen; Kronenberg, Golo; Gertz, Karen; Soderling, Scott H; Miller, Robert H; Barres, Ben A

    2015-07-27

    Myelin is essential in vertebrates for the rapid propagation of action potentials, but the molecular mechanisms driving its formation remain largely unknown. Here we show that the initial stage of process extension and axon ensheathment by oligodendrocytes requires dynamic actin filament assembly by the Arp2/3 complex. Unexpectedly, subsequent myelin wrapping coincides with the upregulation of actin disassembly proteins and rapid disassembly of the oligodendrocyte actin cytoskeleton and does not require Arp2/3. Inducing loss of actin filaments drives oligodendrocyte membrane spreading and myelin wrapping in vivo, and the actin disassembly factor gelsolin is required for normal wrapping. We show that myelin basic protein, a protein essential for CNS myelin wrapping whose role has been unclear, is required for actin disassembly, and its loss phenocopies loss of actin disassembly proteins. Together, these findings provide insight into the molecular mechanism of myelin wrapping and identify it as an actin-independent form of mammalian cell motility. PMID:26166300

  9. Inhibition of C5a receptor alleviates experimental CNS lupus

    PubMed Central

    Jacob, Alexander; Hack, Bradley; Bai, Tao; Brorson, James R.; Quigg, Richard J.; Alexander, Jessy J.

    2010-01-01

    To investigate the role of C5a generated on complement activation in brain, the lupus model, MRL/lpr mice were treated with C5a receptor(R) antagonist (ant). Neutrophil infiltration, ICAM, TNF-α and iNOS mRNA expression, neuronal apoptosis and the expression of p-JNK, pSTAT1 and p-Erk were reduced and p-Akt increased on C5aR inhibition in MRL/lpr brains. MRL/lpr serum caused increased apoptosis in neurons showing that lupus had a direct effect on these cells. C5aRant pretreatment prevented the lupus serum induced loss of neuronal cells. Our findings demonstrate for the first time that C5a/C5aR signaling plays an important role in the pathogenesis of CNS lupus. PMID:20207017

  10. Identification of the role of C/EBP in neurite regeneration following microarray analysis of a L. stagnalis CNS injury model

    PubMed Central

    2012-01-01

    Background Neuronal regeneration in the adult mammalian central nervous system (CNS) is severely compromised due to the presence of extrinsic inhibitory signals and a reduced intrinsic regenerative capacity. In contrast, the CNS of adult Lymnaea stagnalis (L. stagnalis), a freshwater pond snail, is capable of spontaneous regeneration following neuronal injury. Thus, L. stagnalis has served as an animal model to study the cellular mechanisms underlying neuronal regeneration. However, the usage of this model has been limited due to insufficient molecular tools. We have recently conducted a partial neuronal transcriptome sequencing project and reported over 10,000 EST sequences which allowed us to develop and perform a large-scale high throughput microarray analysis. Results To identify genes that are involved in the robust regenerative capacity observed in L. stagnalis, we designed the first gene chip covering ~15, 000 L. stagnalis CNS EST sequences. We conducted microarray analysis to compare the gene expression profiles of sham-operated (control) and crush-operated (regenerative model) central ganglia of adult L. stagnalis. The expression levels of 348 genes were found to be significantly altered (p < 0.05) following nerve injury. From this pool, 67 sequences showed a greater than 2-fold change: 42 of which were up-regulated and 25 down-regulated. Our qPCR analysis confirmed that CCAAT enhancer binding protein (C/EBP) was up-regulated following nerve injury in a time-dependent manner. In order to test the role of C/EBP in regeneration, C/EBP siRNA was applied following axotomy of cultured Lymnaea PeA neurons. Knockdown of C/EBP following axotomy prevented extension of the distal, proximal and intact neurites. In vivo knockdown of C/EBP postponed recovery of locomotory activity following nerve crush. Taken together, our data suggest both somatic and local effects of C/EBP are involved in neuronal regeneration. Conclusions This is the first high-throughput microarray

  11. CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes

    PubMed Central

    Bechler, Marie E.; Byrne, Lauren; ffrench-Constant, Charles

    2015-01-01

    Summary Since Río-Hortega’s description of oligodendrocyte morphologies nearly a century ago, many studies have observed myelin sheath-length diversity between CNS regions [1–3]. Myelin sheath length directly impacts axonal conduction velocity by influencing the spacing between nodes of Ranvier. Such differences likely affect neural signal coordination and synchronization [4]. What accounts for regional differences in myelin sheath lengths is unknown; are myelin sheath lengths determined solely by axons or do intrinsic properties of different oligodendrocyte precursor cell populations affect length? The prevailing view is that axons provide molecular cues necessary for oligodendrocyte myelination and appropriate sheath lengths. This view is based upon the observation that axon diameters correlate with myelin sheath length [1, 5, 6], as well as reports that PNS axonal neuregulin-1 type III regulates the initiation and properties of Schwann cell myelin sheaths [7, 8]. However, in the CNS, no such instructive molecules have been shown to be required, and increasing in vitro evidence supports an oligodendrocyte-driven, neuron-independent ability to differentiate and form initial sheaths [9–12]. We test this alternative signal-independent hypothesis—that variation in internode lengths reflects regional oligodendrocyte-intrinsic properties. Using microfibers, we find that oligodendrocytes have a remarkable ability to self-regulate the formation of compact, multilamellar myelin and generate sheaths of physiological length. Our results show that oligodendrocytes respond to fiber diameters and that spinal cord oligodendrocytes generate longer sheaths than cortical oligodendrocytes on fibers, co-cultures, and explants, revealing that oligodendrocytes have regional identity and generate different sheath lengths that mirror internodes in vivo. PMID:26320951

  12. Novel approaches and challenges to treatment of CNS viral infections

    PubMed Central

    Nath, Avindra; Tyler, Kenneth L.

    2014-01-01

    Existing and emerging viral CNS infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus. Development of new therapies has been hampered by the lack of appropriate animal model systems for some important viruses and by the difficulty in conducting human clinical trials for diseases that may be rare, or in the case of arboviral infections, often have variable seasonal and geographic incidence. Nonetheless, many novel approaches to antiviral therapy are available including candidate thiazolide and purazinecarboxamide derivatives with potential broad-spectrum antiviral efficacy. New herpesvirus drugs include viral helicase-primase and terminase inhibitors. The use of antisense oligonucleotides and other strategies to interfere with viral RNA translation has shown efficacy in experimental models of CNS viral disease. Identifying specific molecular targets within viral replication cycles has led to many existing antivirals and will undoubtedly continue to be the basis of future drug design. A promising new area of research involves therapies based on enhanced understanding of host antiviral immune responses. Toll-like receptor agonists, and drugs that inhibit specific cytokines as well as interferon preparations have all shown potential therapeutic efficacy. Passive transfer of virus-specific cytotoxic T-lymphocytes have been used in humans and may provide an effective therapies for some herpesvirus infections and potentially for progressive multifocal leukoencephalopathy. Humanized monoclonal antibodies directed against specific viral proteins have been developed and in several cases evaluated in humans in settings including West Nile virus and HIV infection and in pre-exposure prophylaxis for rabies. PMID:23913580

  13. Identification of Genetic Determinants of the Sexual Dimorphism in CNS Autoimmunity

    PubMed Central

    Bearoff, Frank; Case, Laure K.; Krementsov, Dimitry N.; Wall, Emma H.; Saligrama, Naresha; Blankenhorn, Elizabeth P.; Teuscher, Cory

    2015-01-01

    Multiple sclerosis (MS) is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, with higher prevalence in females, and a strong genetic component. While over 200 MS susceptibility loci have been identified in GWAS, the underlying mechanisms whereby they contribute to disease susceptibility remains ill-defined. Forward genetics approaches using conventional laboratory mouse strains are useful in identifying and functionally dissecting genes controlling disease-relevant phenotypes, but are hindered by the limited genetic diversity represented in such strains. To address this, we have combined the powerful chromosome substitution (consomic) strain approach with the genetic diversity of a wild-derived inbred mouse strain. Using experimental allergic encephalomyelitis (EAE), a mouse model of MS, we evaluated genetic control of disease course among a panel of 26 consomic strains of mice inheriting chromosomes from the wild-derived PWD strain on the C57BL/6J background, which models the genetic diversity seen in human populations. Nineteen linkages on 18 chromosomes were found to harbor loci controlling EAE. Of these 19 linkages, six were male-specific, four were female-specific, and nine were non-sex-specific, consistent with a differential genetic control of disease course between males and females. An MS-GWAS candidate-driven bioinformatic analysis using orthologous genes linked to EAE course identified sex-specific and non-sex-specific gene networks underlying disease pathogenesis. An analysis of sex hormone regulation of genes within these networks identified several key molecules, prominently including the MAP kinase family, known hormone-dependent regulators of sex differences in EAE course. Importantly, our results provide the framework by which consomic mouse strains with overall genome-wide genetic diversity, approximating that seen in humans, can be used as a rapid and powerful tool for

  14. Variation and constraint in Hox gene evolution.

    PubMed

    Heffer, Alison; Xiang, Jie; Pick, Leslie

    2013-02-01

    Despite enormous body plan variation, genes regulating embryonic development are highly conserved. Here, we probe the mechanisms that predispose ancient regulatory genes to reutilization and diversification rather than evolutionary loss. The Hox gene fushi tarazu (ftz) arose as a homeotic gene but functions as a pair-rule segmentation gene in Drosophila. ftz shows extensive variation in expression and protein coding regions but has managed to elude loss from arthropod genomes. We asked what properties prevent this loss by testing the importance of different protein motifs and partners in the developing CNS, where ftz expression is conserved. Drosophila Ftz proteins with mutated protein motifs were expressed under the control of a neurogenic-specific ftz cis-regulatory element (CRE) in a ftz mutant background rescued for segmentation defects. Ftz CNS function did not require the variable motifs that mediate differential cofactor interactions involved in homeosis or segmentation, which vary in arthropods. Rather, CNS function did require the shared DNA-binding homeodomain, which plays less of a role in Ftz segmentation activity. The Antennapedia homeodomain substituted for Ftz homeodomain function in the Drosophila CNS, but full-length Antennapedia did not rescue CNS defects. These results suggest that a core CNS function retains ftz in arthropod genomes. Acquisition of a neurogenic CRE led to ftz expression in unique CNS cells, differentiating its role from neighboring Hox genes, rendering it nonredundant. The inherent flexibility of modular CREs and protein domains allows for stepwise acquisition of new functions, explaining broad retention of regulatory genes during animal evolution. PMID:23341600

  15. MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD)-Novel and Unique Pathological Features

    PubMed Central

    Zhao, Yuhai; Pogue, Aileen I.; Lukiw, Walter J.

    2015-01-01

    Of the approximately ~2.65 × 103 mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS. PMID:26694372

  16. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4.

    PubMed

    Walsh, James T; Hendrix, Sven; Boato, Francesco; Smirnov, Igor; Zheng, Jingjing; Lukens, John R; Gadani, Sachin; Hechler, Daniel; Gölz, Greta; Rosenberger, Karen; Kammertöns, Thomas; Vogt, Johannes; Vogelaar, Christina; Siffrin, Volker; Radjavi, Ali; Fernandez-Castaneda, Anthony; Gaultier, Alban; Gold, Ralf; Kanneganti, Thirumala-Devi; Nitsch, Robert; Zipp, Frauke; Kipnis, Jonathan

    2015-02-01

    A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell-mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4-producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4-deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4+ T cells from wild-type mice, but not from IL-4-deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell-derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4-producing CD4+ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration. PMID:25607842

  17. Expression of α5 integrin rescues fibronectin responsiveness in NT2N CNS neuronal cells

    PubMed Central

    Meland, Marit N.; Herndon, Mary E.; Stipp, Christopher S.

    2010-01-01

    The extracellular matrix protein fibronectin is implicated in neuronal regeneration in the peripheral nervous system. In the central nervous system (CNS), fibronectin is upregulated at sites of penetrating injuries and stroke; however, CNS neurons downregulate the fibronectin receptor, α5β1 integrin, during differentiation and generally respond poorly to fibronectin. NT2N CNS neuron-like cells (derived from NT2 precursor cells) have been used in pre-clinical and clinical studies for treatment of stroke and a variety of CNS injury and disease models. Here we show that, like primary CNS neurons, NT2N cells downregulate α5β1 integrin during differentiation and respond poorly to fibronectin. The poor neurite outgrowth by NT2N cells on fibronectin can be rescued by transducing NT2 precursors with a retroviral vector expressing α5 integrin under the control of the Murine Stem Cell Virus 5′ long terminal repeat. Sustained α5 integrin expression is compatible with the CNS-like neuronal differentiation of NT2N cells and does not prevent robust neurite outgrowth on other integrin ligands. Thus, α5 integrin expression in CNS neuronal precursor cells may provide a strategy for enhancing the outgrowth and survival of implanted cells in cell replacement therapies for CNS injury and disease. PMID:19598247

  18. Safety Evaluation of CNS Administered Biologics-Study Design, Data Interpretation, and Translation to the Clinic.

    PubMed

    Vuillemenot, Brian R; Korte, Sven; Wright, Teresa L; Adams, Eric L; Boyd, Robert B; Butt, Mark T

    2016-07-01

    Many central nervous system (CNS) diseases are inadequately treated by systemically administered therapies due to the blood brain barrier (BBB), which prevents achieving adequate drug concentrations at sites of action. Due to the increasing prevalence of neurodegenerative diseases and the inability of most systemically administered therapies to cross the BBB, direct CNS delivery will likely play an increasing role in treatment. Administration of large molecules, cells, viral vectors, oligonucleotides, and other novel therapies directly to the CNS via the subarachnoid space, ventricular system, or parenchyma overcomes this obstacle. Clinical experience with direct CNS administration of small molecule therapies suggests that this approach may be efficacious for the treatment of neurodegenerative disorders using biological therapies. Risks of administration into the brain tissue or cerebrospinal fluid include local damage from implantation of the delivery system and/or administration of the therapeutic and reactions affecting the CNS. Preclinical safety studies on CNS administered compounds must differentiate between the effects of the test article, the delivery device, and/or the vehicle, and assess exacerbations of reactions due to combinations of effects. Animal models characterized for safety assessment of CNS administered therapeutics have enabled human trials, but interpretation can be challenging. This manuscript outlines the challenges of preclinical intrathecal/intracerebroventricular/intraparenchymal studies, evaluation of results, considerations for special endpoints, and translation of preclinical findings to enable first-in-human trials. Recommendations will be made based on the authors' collective experience with conducting these studies to enable clinical development of CNS-administered biologics. PMID:27354708

  19. CNS species and antimicrobial resistance in clinical and subclinical bovine mastitis.

    PubMed

    Waller, K Persson; Aspán, A; Nyman, A; Persson, Y; Andersson, U Grönlund

    2011-08-26

    Coagulase-negative staphylococci (CNS) are often associated with bovine mastitis. Knowledge about the relative importance of specific CNS species in different types of mastitis, and differences in antimicrobial resistance among CNS species is, however, scarce. Therefore, the aims of this study were to compare prevalence and antimicrobial susceptibility of CNS species in clinical and subclinical mastitis using material from two national surveys. Overall, Staphylococcus chromogenes and Staphylococcus epidermidis were the most common CNS species found followed by Staphylococcus simulans and Staphylococcus haemolyticus. S. epidermidis was significantly more prevalent in subclinical than in clinical mastitis, and a similar trend was observed for Staphylococcus saprophyticus, while Staphylococcus hyicus was significantly more common in clinical mastitis. The prevalence of β-lactamase producing isolates varied markedly between CNS species, and was significantly higher in S. epidermidis and S. haemolyticus (∼ 40%), than in S. simulans and S. chromogenes where none or a few of the isolates produced β-lactamase. Resistance to more than one antimicrobial substance occurred in 9% and 7% of the clinical and subclinical isolates, respectively. In conclusion, the distribution of CNS species differed between clinical and subclinical mastitis indicating inter-species variation of pathogenicity and epidemiology. Overall, the prevalence of antimicrobial resistance was low, but some variation between CNS species was observed. PMID:21561725

  20. Perioperatively acquired disorders of coagulation

    PubMed Central

    Grottke, Oliver; Fries, Dietmar; Nascimento, Bartolomeu

    2015-01-01

    Purpose of review To provide an overview of acquired coagulopathies that can occur in various perioperative clinical settings. Also described are coagulation disturbances linked to antithrombotic medications and currently available strategies to reverse their antithrombotic effects in situations of severe hemorrhage. Recent findings Recent studies highlight the link between low fibrinogen and decreased fibrin polymerization in the development of acquired coagulopathy. Particularly, fibrin(ogen) deficits are observable after cardiopulmonary bypass in cardiac surgery, on arrival at the emergency room in trauma patients, and with ongoing bleeding after child birth. Regarding antithrombotic therapy, although new oral anticoagulants offer the possibility of efficacy and relative safety compared with vitamin K antagonists, reversal of their anticoagulant effect with nonspecific agents, including prothrombin complex concentrate, has provided conflicting results. Specific antidotes, currently being developed, are not yet licensed for clinical use, but initial results are promising. Summary Targeted hemostatic therapy aims to correct coagulopathies in specific clinical settings, and reduce the need for allogeneic transfusions, thus preventing massive transfusion and its deleterious outcomes. Although there are specific guidelines for reversing anticoagulation in patients treated with antiplatelet agents or warfarin, there is currently little evidence to advocate comprehensive recommendations to treat drug-induced coagulopathy associated with new oral anticoagulants. PMID:25734869

  1. Foodborne listeriosis acquired in hospitals.

    PubMed

    Silk, Benjamin J; McCoy, Morgan H; Iwamoto, Martha; Griffin, Patricia M

    2014-08-15

    Listeriosis is characterized by bacteremia or meningitis. We searched for listeriosis case series and outbreak investigations published in English by 2013, and assessed the strength of evidence for foodborne acquisition among patients who ate hospital food. We identified 30 reports from 13 countries. Among the case series, the median proportion of cases considered to be hospital-acquired was 25% (range, 9%-67%). The median number of outbreak-related illnesses considered to be hospital-acquired was 4.0 (range, 2-16). All patients were immunosuppressed in 18 of 24 (75%) reports with available data. Eight outbreak reports with strong evidence for foodborne acquisition in a hospital implicated sandwiches (3 reports), butter, precut celery, Camembert cheese, sausage, and tuna salad (1 report each). Foodborne acquisition of listeriosis among hospitalized patients is well documented internationally. The number of listeriosis cases could be reduced substantially by establishing hospital policies for safe food preparation for immunocompromised patients and by not serving them higher-risk foods. PMID:24846635

  2. [MicroRNAs in microglia polarization and CNS diseases: mechanism and functions].

    PubMed

    Fang, Xue; Tan, Wei-Xing; He, Cheng; Cao, Li

    2015-02-25

    Microglia are resident macrophages of central nervous system (CNS), and thus act as the crucial stuff of immune response and play very important roles in the progress of various CNS diseases. There are two different polarization statuses of activated microglia, M1 and M2 phenotypes. M1 polarized microglia are important for eradicating bacterial and promoting inflammation, whereas M2 cells are characterized by anti-inflammation and tissue remodeling. Recently, more and more evidence indicated that different polarized microglia showed diverse microRNA (miRNA) expression profiles. MiRNAs regulate microglia polarization, and thus affect the progress of CNS diseases. Fully exploring the polarization status of microglia during CNS diseases and the role of miRNAs in microglia polarization will be very helpful for a deep understanding of the roles of microglia in immunopathologic mechanism of different CNS diseases and offer the theoretical foundation of searching more effective therapies for these disorders. PMID:25672624

  3. Current approaches to enhance CNS delivery of drugs across the brain barriers

    PubMed Central

    Lu, Cui-Tao; Zhao, Ying-Zheng; Wong, Ho Lun; Cai, Jun; Peng, Lei; Tian, Xin-Qiao

    2014-01-01

    Although many agents have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed. PMID:24872687

  4. Neuron-specific SALM5 limits inflammation in the CNS via its interaction with HVEM

    PubMed Central

    Zhu, Yuwen; Yao, Sheng; Augustine, Mathew M.; Xu, Haiying; Wang, Jun; Sun, Jingwei; Broadwater, Megan; Ruff, William; Luo, Liqun; Zhu, Gefeng; Tamada, Koji; Chen, Lieping

    2016-01-01

    The central nervous system (CNS) is an immune-privileged organ with the capacity to prevent excessive inflammation. Aside from the blood-brain barrier, active immunosuppressive mechanisms remain largely unknown. We report that a neuron-specific molecule, synaptic adhesion-like molecule 5 (SALM5), is a crucial contributor to CNS immune privilege. We found that SALM5 suppressed lipopolysaccharide-induced inflammatory responses in the CNS and that a SALM-specific monoclonal antibody promoted inflammation in the CNS, and thereby aggravated clinical symptoms of mouse experimental autoimmune encephalomyelitis. In addition, we identified herpes virus entry mediator as a functional receptor that mediates SALM5’s suppressive function. Our findings reveal a molecular link between the neuronal system and the immune system, and provide potential therapeutic targets for the control of CNS diseases. PMID:27152329

  5. Detection of classical and newly described staphylococcal superantigen genes in coagulase-negative staphylococci isolated from bovine intramammary infections.

    PubMed

    Park, Joo Youn; Fox, Lawrence K; Seo, Keun Seok; McGuire, Mark A; Park, Yong Ho; Rurangirwa, Fred R; Sischo, William M; Bohach, Gregory A

    2011-01-10

    The coagulase-negative staphylococci (CNS) are the most prevalent mastitis pathogen group yet their virulence characteristics have not been well described. We investigated the presence of 19 classical and newly described staphylococcal superantigen (SAg) genes in CNS isolates from bovine intramammary infections (IMI). A total of 263 CNS representing 11 different Staphylococcus spp. were examined, and 31.2% (n=82) of CNS isolates had one or more SAg genes; there were 21 different SAg gene combinations. The most prevalent combination of SAg genes (seb, seln and selq; n=45) was found in S. chromogenes, S. xylosus, S. haemolyticus, S. sciuri subsp. carnaticus, S. simulans and S. succinus. The genes for SAgs appear to be widely distributed amongst CNS isolated from bovine IMI. PMID:20667668

  6. The role of oligodendrocytes and oligodendrocyte progenitors in CNS remyelination.

    PubMed

    Keirstead, H S; Blakemore, W F

    1999-01-01

    Remyelination enables restoration of saltatory conduction and a return of normal function lost during demyelination. Unfortunately, remyelination is often incomplete in the adult human central nervous system (CNS) and this failure of remyelination is one of the main reasons for clinical deficits in demyelinating disease. An understanding of the failure of remyelination in demyelinating diseases such as Multiple Sclerosis depends upon the elucidation of cellular events underlying successful remyelination. Although the potential for remyelination of the adult CNS has been well established, there is still some dispute regarding the origin of the remyelinating cell population. The literature variously reports that remyelinating oligodendrocytes arise from dedifferentiation and/or proliferation of mature oligodendrocytes, or are generated solely from proliferation and differentiation of glial progenitor cells. This review focuses on studies carried out on remyelinating lesions in the adult rat spinal cord produced by injection of antibodies to galactocerebroside plus serum complement that demonstrate: 1) oligodendrocytes which survive within an area of demyelination do not contribute to remyelination, 2) remyelination is carried out by oligodendrocyte progenitor cells, 3) recruitment of oligodendrocyte progenitors to an area of demyelination is a local response, and 4) division of oligodendrocyte progenitors is symmetrical and results in chronic depletion of the oligodendrocyte progenitor population in the normal white matter around an area of remyelination. These results suggest that failure of remyelination may be contributed to by a depletion of oligodendrocyte progenitors especially following repeated episodes of demyelination. Remyelination allows the return of saltatory conduction (Smith et al., 1979) and the functional recovery of demyelination-induced deficits (Jeffery et al., 1997). Findings such as these have encouraged research aimed at enhancing the limited

  7. Acquired immunodeficiency syndrome: neuroradiologic findings.

    PubMed

    Kelly, W M; Brant-Zawadzki, M

    1983-11-01

    Central nervous system complications depicted by CT in ten patients with acquired immunodeficiency syndrome are described. Three patients had multifocal intra-axial enhancing lesions representing atypical brain abscesses (two with toxoplasmosis, one with candidiasis). A fourth patient with multifocal "ring" lesions whose biopsy was interpreted as suggestive of toxoplasmosis responded poorly to treatment. Following his death three months later of Pneumocystis carinii pneumonia, autopsy revealed primary intracerebral immunoblastic lymphoma. One patient had Kaposi sarcoma involving the right frontal lobe (seen as an enhancing mass on the CT scan). CT findings in the remaining five patients revealed mild to moderate enlargement of cerebrospinal fluid spaces (including ventricles and basal cisternae) as a result of cryptococcal meningitis in three patients and "aseptic" meningitis in two. The two patients in whom early biopsy confirmed toxoplasmosis responded well to anti-infective therapy, resulting in dramatic clinical recoveries. PMID:6622693

  8. Bejel: acquirable only in childhood?

    PubMed

    Rothschild, Bruce M; Rothschild, Christine; Naples, Virginia; Billard, Michel; Panero, Barbara

    2006-10-01

    Bejel clearly has a long history in the Middle East and the Sudan, but was it transmitted to Europe? As the major manifestation of bejel is presence of periosteal reaction in 20-40% of afflicted populations, absence of significant population frequency of periosteal reaction in Europe would exclude that diagnosis. Examination of skeletal populations from continental Europe revealed no significant periosteal reaction at the time of and immediately subsequent to the Crusades. Thus, there is no evidence for bejel in Europe, in spite of clear contact (the mechanism of bejel transmission in children) between warring groups, at least during the Crusades. This supports the hypothesis that bejel is a childhood-acquired disease and apparently cannot be contracted in adulthood. PMID:17049474

  9. Lymphoma in acquired generalized lipodystrophy.

    PubMed

    Brown, Rebecca J; Chan, Jean L; Jaffe, Elaine S; Cochran, Elaine; DePaoli, Alex M; Gautier, Jean-Francois; Goujard, Cecile; Vigouroux, Corinne; Gorden, Phillip

    2016-01-01

    Acquired generalized lipodystrophy (AGL) is a rare disease thought to result from autoimmune destruction of adipose tissue. Peripheral T-cell lymphoma (PTCL) has been reported in two AGL patients. We report five additional cases of lymphoma in AGL, and analyze the role of underlying autoimmunity and recombinant human leptin (metreleptin) replacement in lymphoma development. Three patients developed lymphoma during metreleptin treatment (two PTCL and one ALK-positive anaplastic large cell lymphoma), and two developed lymphomas (mycosis fungoides and Burkitt lymphoma) without metreleptin. AGL is associated with high risk for lymphoma, especially PTCL. Autoimmunity likely contributes to this risk. Lymphoma developed with or without metreleptin, suggesting metreleptin does not directly cause lymphoma development; a theoretical role of metreleptin in lymphoma progression remains possible. For most patients with AGL and severe metabolic complications, the proven benefits of metreleptin on metabolic disease will likely outweigh theoretical risks of metreleptin in lymphoma development or progression. PMID:25864863

  10. Modern cerebrospinal fluid analyses for the diagnosis of diffuse large B-cell lymphoma of the CNS.

    PubMed

    Baraniskin, Alexander; Schroers, Roland

    2014-01-01

    CNS lymphomas represent rare and aggressive variants of extranodal non-Hodgkin's lymphomas, which may present with diverse neurological symptoms and are often diagnostically challenging. Primary CNS lymphomas develop within the CNS and characteristically involve the brain, leptomeninges, eyes and, in rare cases, spinal cord. Secondary CNS lymphomas are characterized by expansion of systemic lymphomas to the CNS. Multimodal investigation of cerebrospinal fluid (CSF) comprises an important component of the diagnostic work-up for patients with suspected CNS lymphomas. Cytopathological examination of the CSF is still regarded as the 'gold standard' for the diagnosis of leptomeningeal malignant disease. However, cytopathology has only a low sensitivity in detecting leptomeningeal lymphoma involvement. Modern technologies including proteochemical and immunophenotypic studies by flow cytometry, and molecular genetic analyses of CSF may increase sensitivity and specificity, therefore, facilitating the diagnosis of CNS lymphomas. This review gives an overview and discussion of the current aspects of CSF analyses in CNS lymphomas. PMID:25054902

  11. Infantile and acquired nystagmus in childhood.

    PubMed

    Ehrt, Oliver

    2012-11-01

    Nystagmus is an involuntary, periodic eye movement caused by a slow drift of fixation which is followed by a fast refixation saccade (jerk nystagmus) or a slow movement back to fixation (pendular nystagmus). In childhood most cases are benign forms of nystagmus: idiopathic infantile, ocular or latent nystagmus. They arise at the age of 3 months, without oscillopsia and show the absence of the physiologic opto-kinetic nystagmus. A full ophthalmologic evaluation is all that is needed in most cases: albinism, macular or optic nerve hypoplasia and congenital retinal dystrophies are the most common forms of ocular nystagmus. Idiopathic infantile nystagmus can be hereditary, the most common and best analyzed form being a mutation of the FRMD7 gene on chromosome Xq26.2. The mutation shows a mild genotype-phenotype correlation. In all female carriers the opto-kinetic nystagmus is absent and half had mild nystagmus. Latent nystagmus is part of the infantile esotropia syndrome and shows the unique feature of change of direction when the fixing eye changes: it is always beating to the side of the fixing eye. There is no cure for infantile nystagmus but therapeutic options include magnifying visual aids or eye muscle surgery at the age of 6-8 y in patients with head turn. Less than 20% of childhood nystagmus are acquired and need further neurological and imaging work-up. Alarming signs and symptoms are: onset after the age of 4 months, oscillopsia, dissociated (asymmetric) nystagmus, preserved opto-kinetic nystagmus, afferent pupillary defect, papilloedema and neurological symptoms like vertigo and nausea. The most common cause is due to pathology of the anterior optic pathway (e.g. optic nerve gliomas). It shows the same clinical feature of dissociated nystagmus as spasmus nutans but has a higher frequency as in INO. Other forms of acquired nystagmus are due to brainstem, cerebellar or metabolic diseases. PMID:22459007

  12. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  13. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  14. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  15. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  16. Functional equivalence of Hox gene products in the specification of the tritocerebrum during embryonic brain development of Drosophila.

    PubMed

    Hirth, F; Loop, T; Egger, B; Miller, D F; Kaufman, T C; Reichert, H

    2001-12-01

    Hox genes encode evolutionarily conserved transcription factors involved in the specification of segmental identity during embryonic development. This specification of identity is thought to be directed by differential Hox gene action, based on differential spatiotemporal expression patterns, protein sequence differences, interactions with co-factors and regulation of specific downstream genes. During embryonic development of the Drosophila brain, the Hox gene labial is required for the regionalized specification of the tritocerebral neuromere; in the absence of labial, the cells in this brain region do not acquire a neuronal identity and major axonal pathfinding deficits result. We have used genetic rescue experiments to investigate the functional equivalence of the Drosophila Hox gene products in the specification of the tritocerebral neuromere. Using the Gal4-UAS system, we first demonstrate that the labial mutant brain phenotype can be rescued by targeted expression of the Labial protein under the control of CNS-specific labial regulatory elements. We then show that under the control of these CNS-specific regulatory elements, all other Drosophila Hox gene products, except Abdominal-B, are able to efficiently replace Labial in the specification of the tritocerebral neuromere. We also observe a correlation between the rescue efficiency of the Hox proteins and the chromosomal arrangement of their encoding loci. Our results indicate that, despite considerably diverged sequences, most Hox proteins are functionally equivalent in their ability to replace Labial in the specification of neuronal identity. This suggests that in embryonic brain development, differences in Hox gene action rely mainly on cis-acting regulatory elements and not on Hox protein specificity. PMID:11731458

  17. Members of the bHLH-PAS family regulate Shh transcription in forebrain regions of the mouse CNS.

    PubMed

    Epstein, D J; Martinu, L; Michaud, J L; Losos, K M; Fan, C; Joyner, A L

    2000-11-01

    The secreted protein sonic hedgehog (Shh) is required to establish patterns of cellular growth and differentiation within ventral regions of the developing CNS. The expression of Shh in the two tissue sources responsible for this activity, the axial mesoderm and the ventral midline of the neural tube, is regulated along the anteroposterior neuraxis. Separate cis-acting regulatory sequences have been identified which direct Shh expression to distinct regions of the neural tube, supporting the view that multiple genes are involved in activating Shh transcription along the length of the CNS. We show here that the activity of one Shh enhancer, which directs reporter expression to portions of the ventral midbrain and diencephalon, overlaps both temporally and spatially with the expression of Sim2. Sim2 encodes a basic helix-loop-helix (bHLH-PAS) PAS domain containing transcriptional regulator whose Drosophila homolog, single-minded, is a master regulator of ventral midline development. Both vertebrate and invertebrate Sim family members were found sufficient for the activation of the Shh reporter as well as endogenous Shh mRNA. Although Shh expression is maintained in Sim2(-)(/)(-) embryos, it was determined to be absent from the rostral midbrain and caudal diencephalon of embryos carrying a dominant-negative transgene that disrupts the function of bHLH-PAS proteins. Together, these results suggest that bHLH-PAS family members are required for the regulation of Shh transcription within aspects of the ventral midbrain and diencephalon. PMID:11023872

  18. Maternal immune activation and abnormal brain development across CNS disorders.

    PubMed

    Knuesel, Irene; Chicha, Laurie; Britschgi, Markus; Schobel, Scott A; Bodmer, Michael; Hellings, Jessica A; Toovey, Stephen; Prinssen, Eric P

    2014-11-01

    Epidemiological studies have shown a clear association between maternal infection and schizophrenia or autism in the progeny. Animal models have revealed maternal immune activation (mIA) to be a profound risk factor for neurochemical and behavioural abnormalities in the offspring. Microglial priming has been proposed as a major consequence of mIA, and represents a critical link in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or aged offspring. Such diversity of phenotypic outcomes in the mIA model are mirrored by recent clinical evidence suggesting that infectious exposure during pregnancy is also associated with epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical research also suggests that mIA might precipitate the development of Alzheimer and Parkinson diseases. Here, we summarize and critically review the emerging evidence that mIA is a shared environmental risk factor across CNS disorders that varies as a function of interactions between genetic and additional environmental factors. We also review ongoing clinical trials targeting immune pathways affected by mIA that may play a part in disease manifestation. In addition, future directions and outstanding questions are discussed, including potential symptomatic, disease-modifying and preventive treatment strategies. PMID:25311587

  19. Attention deficit hyperactivity disorder, CNS stimulants and sport.

    PubMed

    Hickey, G; Fricker, P

    1999-01-01

    Attention deficit hyperactivity disorder (ADHD) affects 1 to 10% of children and is characterised by a persistent pattern of inattention and/or hyperactivity/impulsivity. Over one-half of children with ADHD have associated conditions, including learning disabilities, conduct disorders, poor coordination, depression, anxiety, obsessive-compulsive disorders and bipolar disorders. CNS stimulant medication used in the management of ADHD is not permitted for use in competition by the International Olympic Committee (IOC) and this poses a problem for the physicians of patients with ADHD. On the one hand, attention and concentration are improved by stimulant medication and fine motor coordination and balance are improved after methylphenidate administration, but these therapeutic and sport-related benefits are not available to the athlete with ADHD who wishes to compete under IOC rules. It has been suggested that treatment with methylphenidate may be suitable for athletes with ADHD, as cessation of therapy 24 hours before competition is usually adequate to allow drug clearance which should avoid a positive result being returned on drug testing. More research is needed to establish whether stimulant medication for athletes with ADHD provides an unfair advantage in competition. PMID:10028130

  20. Role of Hemichannels in CNS Inflammation and the Inflammasome Pathway.

    PubMed

    Kim, Yuri; Davidson, Joanne O; Gunn, Katherine C; Phillips, Anthony R; Green, Colin R; Gunn, Alistair J

    2016-01-01

    Neurodegenerative, cardiovascular, and metabolic disorders, once triggered, share a number of common features, including sustained inflammatory cell activation and vascular disruption. These shared pathways are induced independently of any genetic predisposition to the disease or the precise external stimulus. Glial cells respond to injury with an innate immune response that includes release of proinflammatory cytokines and chemokines. Vascular endothelial cells may also be affected, leading to opening of the blood-brain barrier that facilitates invasion by circulating inflammatory cells. Inflammation can trigger acute neural injury followed by chronic inflammation that plays a key role in neurodegenerative conditions. Gap junction channels normally allow direct cell-to-cell communication. They are formed by the docking of two hemichannels, one contributed by each of the neighboring cells. While the opening probability of these channels is tightly controlled under resting conditions, hemichannels can open in response to injury or inflammatory factors, forming a large, relatively nonselective membrane pore. In this review, we consider the CNS immune system from the perspective that modulating connexin hemichannel opening can prevent tissue damage arising from excessive and uncontrolled inflammation. We discuss connexin channel roles in microglia, astrocytes, and endothelial cells in both acute and chronic inflammatory conditions, and in particular describe the role of connexin hemichannels in the inflammasome pathway where they contribute to both its activation and its spread to neighboring cells. Finally, we describe the benefits of hemichannel block in animal models of brain injury. PMID:27038371

  1. Role of galectin-3 in prion infections of the CNS

    SciTech Connect

    Mok, Simon W.F.; Riemer, Constanze; Madela, Kazimierz; Hsu, Daniel K.; Liu, Fu-Tong; Gueltner, Sandra; Heise, Ines; Baier, Michael . E-mail: baierm@rki.de

    2007-08-03

    Galectin-3 is a multi-functional protein and participates in mediating inflammatory reactions. The pronounced overexpression of galectin-3 in prion-infected brain tissue prompted us to study the role of this protein in a murine prion model. Immunofluorescence double-labelling identified microglia as the major cell type expressing galectin-3. Ablation of galectin-3 did not affect PrP{sup Sc}-deposition and development of gliosis. However, galectin-3{sup -/-}-mice showed prolonged survival times upon intracerebral and peripheral scrapie infections. Moreover, protein levels of the lysosomal activation marker LAMP-2 were markedly reduced in prion-infected galectin-3{sup -/-}-mice suggesting a role of galectin-3 in regulation of lysosomal functions. Lower mRNA levels of Beclin-1 and Atg5 in prion-infected wild-type and galectin-3{sup -/-}-mice indicated an impairment of autophagy although autophagosome formation was unchanged. The results point towards a detrimental role of galectin-3 in prion infections of the CNS and suggest that endo-/lysosomal dysfunction in combination with reduced autophagy may contribute to disease development.

  2. Fluids and barriers of the CNS: a historical viewpoint

    PubMed Central

    2011-01-01

    Tracing the exact origins of modern science can be a difficult but rewarding pursuit. It is possible for the astute reader to follow the background of any subject through the many important surviving texts from the classical and ancient world. While empirical investigations have been described by many since the time of Aristotle and scientific methods have been employed since the Middle Ages, the beginnings of modern science are generally accepted to have originated during the 'scientific revolution' of the 16th and 17th centuries in Europe. The scientific method is so fundamental to modern science that some philosophers consider earlier investigations as 'pre-science'. Notwithstanding this, the insight that can be gained from the study of the beginnings of a subject can prove important in the understanding of work more recently completed. As this journal undergoes an expansion in focus and nomenclature from cerebrospinal fluid (CSF) into all barriers of the central nervous system (CNS), this review traces the history of both the blood-CSF and blood-brain barriers from as early as it was possible to find references, to the time when modern concepts were established at the beginning of the 20th century. PMID:21349150

  3. Carbon monoxide and the CNS: challenges and achievements

    PubMed Central

    Queiroga, Cláudia S F; Vercelli, Alessandro; Vieira, Helena L A

    2015-01-01

    Haem oxygenase (HO) and its product carbon monoxide (CO) are associated with cytoprotection and maintenance of homeostasis in several different organs and tissues. This review focuses upon the role of exogenous and endogenous CO (via HO activity and expression) in various CNS pathologies, based upon data from experimental models, as well as from some clinical data on human patients. The pathophysiological conditions reviewed are cerebral ischaemia, chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases), multiple sclerosis and pain. Among these pathophysiological conditions, a variety of cellular mechanisms and processes are considered, namely cytoprotection, cell death, inflammation, cell metabolism, cellular redox responses and vasomodulation, as well as the different targeted neural cells. Finally, novel potential methods and strategies for delivering exogenous CO as a drug are discussed, particularly approaches based upon CO-releasing molecules, their limitations and challenges. The diagnostic and prognostic value of HO expression in clinical use for brain pathologies is also addressed. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6 PMID:24758548

  4. Molecular MRI approaches to the detection of CNS inflammation.

    PubMed

    Sibson, Nicola R; Anthony, Daniel C; van Kasteren, Sander; Dickens, Alex; Perez-Balderas, Francisco; McAteer, Martina A; Choudhury, Robin P; Davis, Benjamin G

    2011-01-01

    Inflammation is a key component of many neurological diseases, yet our understanding of the contribution of these processes to tissue damage remains poor. For many such diseases, magnetic resonance imaging (MRI) has become the method of choice for clinical diagnosis. However, many of the MRI parameters that enable disease detection, such as passive contrast enhancement across a compromised blood-brain barrier, are weighted towards late-stage disease. Moreover, whilst these methods may report on disease severity, they are not able to provide information on either disease activity or the underlying molecular processes. There is a need, therefore, to develop methods that enable earlier disease detection, potentially long before clinical symptoms become apparent, together with identification of specific molecular processes that may guide specific therapy. This chapter describes the methodology for the synthesis and validation of two novel, functional MRI-detectable probes, based on microparticles of iron oxide (MPIO), which target endothelial adhesion molecules. These contrast agents enable the detection of acute brain inflammation in vivo, at a time when pathology is undetectable by conventional MRI. Such molecular MRI methods are opening new vistas for the acute diagnosis of CNS disease, together with the possibility for individually tailored therapy and earlier, more sensitive assessment of the efficacy of novel therapies. PMID:21279613

  5. Stress Preconditioning of Spreading Depression in the Locust CNS

    PubMed Central

    Rodgers, Corinne I.; Armstrong, Gary A. B.; Shoemaker, Kelly L.; LaBrie, John D.; Moyes, Christopher D.; Robertson, R. Meldrum

    2007-01-01

    Cortical spreading depression (CSD) is closely associated with important pathologies including stroke, seizures and migraine. The mechanisms underlying SD in its various forms are still incompletely understood. Here we describe SD-like events in an invertebrate model, the ventilatory central pattern generator (CPG) of locusts. Using K+ -sensitive microelectrodes, we measured extracellular K+ concentration ([K+]o) in the metathoracic neuropile of the CPG while monitoring CPG output electromyographically from muscle 161 in the second abdominal segment to investigate the role K+ in failure of neural circuit operation induced by various stressors. Failure of ventilation in response to different stressors (hyperthermia, anoxia, ATP depletion, Na+/K+ ATPase impairment, K+ injection) was associated with a disturbance of CNS ion homeostasis that shares the characteristics of CSD and SD-like events in vertebrates. Hyperthermic failure was preconditioned by prior heat shock (3 h, 45°C) and induced-thermotolerance was associated with an increase in the rate of clearance of extracellular K+ that was not linked to changes in ATP levels or total Na+/K+ ATPase activity. Our findings suggest that SD-like events in locusts are adaptive to terminate neural network operation and conserve energy during stress and that they can be preconditioned by experience. We propose that they share mechanisms with CSD in mammals suggesting a common evolutionary origin. PMID:18159249

  6. Nicotinic ACh Receptors as Therapeutic Targets in CNS Disorders

    PubMed Central

    Dineley, Kelly T.; Pandya, Anshul A.; Yakel, Jerrel L.

    2015-01-01

    The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor channels (nAChRs). These receptors are widely distributed throughout the central nervous system, being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however the α7 and α4β2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in the mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer’s disease), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain. PMID:25639674

  7. Epsin1 modulates synaptic vesicle retrieval capacity at CNS synapses.

    PubMed

    Kyung, Jae Won; Bae, Jae Ryul; Kim, Dae-Hwan; Song, Woo Keun; Kim, Sung Hyun

    2016-01-01

    Synaptic vesicle retrieval is an essential process for continuous maintenance of neural information flow after synaptic transmission. Epsin1, originally identified as an EPS15-interacting protein, is a major component of clathrin-mediated endocytosis. However, the role of Epsin1 in synaptic vesicle endocytosis at CNS synapses remains elusive. Here, we showed significantly altered synaptic vesicle endocytosis in neurons transfected with shRNA targeting Epsin1 during/after neural activity. Endocytosis was effectively restored by introducing shRNA-insensitive Epsin1 into Epsin1-depleted neurons. Domain studies performed on neurons in which domain deletion mutants of Epsin1 were introduced after Epsin1 knockdown revealed that ENTH, CLAP, and NPFs are essential for synaptic vesicle endocytosis, whereas UIMs are not. Strikingly, the efficacy of the rate of synaptic vesicle retrieval (the "endocytic capacity") was significantly decreased in the absence of Epsin1. Thus, Epsin1 is required for proper synaptic vesicle retrieval and modulates the endocytic capacity of synaptic vesicles. PMID:27557559

  8. Epsin1 modulates synaptic vesicle retrieval capacity at CNS synapses

    PubMed Central

    Kyung, Jae Won; Bae, Jae Ryul; Kim, Dae-Hwan; Song, Woo Keun; Kim, Sung Hyun

    2016-01-01

    Synaptic vesicle retrieval is an essential process for continuous maintenance of neural information flow after synaptic transmission. Epsin1, originally identified as an EPS15-interacting protein, is a major component of clathrin-mediated endocytosis. However, the role of Epsin1 in synaptic vesicle endocytosis at CNS synapses remains elusive. Here, we showed significantly altered synaptic vesicle endocytosis in neurons transfected with shRNA targeting Epsin1 during/after neural activity. Endocytosis was effectively restored by introducing shRNA-insensitive Epsin1 into Epsin1-depleted neurons. Domain studies performed on neurons in which domain deletion mutants of Epsin1 were introduced after Epsin1 knockdown revealed that ENTH, CLAP, and NPFs are essential for synaptic vesicle endocytosis, whereas UIMs are not. Strikingly, the efficacy of the rate of synaptic vesicle retrieval (the “endocytic capacity”) was significantly decreased in the absence of Epsin1. Thus, Epsin1 is required for proper synaptic vesicle retrieval and modulates the endocytic capacity of synaptic vesicles. PMID:27557559

  9. Rumor management in nursing systems: role of the psychiatric CNS.

    PubMed

    Chase, P; Stuart, G W

    1995-11-01

    RUMOR MANAGEMENT AND control is particularly important in nursing systems during times of change. In this article, a brief history of the study of rumor and the rumor process is given and applied to nursing, systems thinking and the CNS, and three types of rumor are described. Examples are given and strategies and approaches for managing rumor are prescribed. The first approach, used when a final decision about a planned change has not been made, helps avoid "trickle down" and builds trust and empowerment by soliciting and using input from those who will be affected by the proposed change. The intent of the second approach, used when a decision has been finalized or an event has occurred and rumor has preceded an official announcement, is to debrief from the occurrence or transform the decision. The last approach is used to interrupt a pattern of misinformation and to clarify or inform. The nurse leader or manager must stay in the communication loop and refrain from blaming a speculated source in order to correct information. PMID:8697379

  10. Posterior reversible encephalopathy syndrome: another manifestation of CNS SLE?

    PubMed

    Ishimori, M L; Pressman, B D; Wallace, D J; Weisman, M H

    2007-01-01

    A variety of neuropsychiatric findings may complicate systemic lupus erythematosus (SLE) and pose diagnostic and therapeutic dilemmas. We describe the clinical and radiographic features of posterior reversible encephalopathy syndrome (PRES) and distinguish PRES from other conditions seen in SLE. Patient charts and magnetic resonance imaging (MRI) findings of four patients with SLE on immunosuppressive therapy with acute or subacute neurologic changes initially suggesting cerebritis or stroke were reviewed. The English language literature was reviewed using the Medline databases from 1996-2006 for other reports of PRES with SLE. Literature review yielded 26 other SLE cases reported with PRES. SLE patients with PRES were more commonly on immunosuppressive drugs, had episodes of relative hypertension, and had renal involvement. Characteristic findings are seen on MRI, which differentiate PRES from other CNS complications of SLE. Clinical and radiographic resolution of abnormalities within 1-4 weeks is typically seen. PRES has been increasingly recognized. Reversible changes are found on brain MRI accompanied by sometimes dramatic signs and symptoms. The therapeutic implications for separating PRES from stroke or cerebritis are important. We propose that PRES should be considered in the differential diagnosis in SLE patients with new-onset neurologic signs and symptoms. PMID:17664235

  11. Database mining applied to central nervous system (CNS) activity.

    PubMed

    Pintore, M; Taboureau, O; Ros, F; Chrétien, J R

    2001-04-01

    A data set of 389 compounds, active in the central nervous system (CNS) and divided into eight classes according to the receptor type, was extracted from the RBI database and analyzed by Self-Organizing Maps (SOM), also known as Kohonen Artificial Neural Networks. This method gives a 2D representation of the distribution of the compounds in the hyperspace derived from their molecular descriptors. As SOM belongs to the category of unsupervised techniques, it has to be combined with another method in order to generate classification models with predictive ability. The fuzzy clustering (FC) approach seems to be particularly suitable to delineate clusters in a rational way from SOM and to get an automatic objective map interpretation. Maps derived by SOM showed specific regions associated with a unique receptor type and zones in which two or more activity classes are nested. Then, the modeling ability of the proposed SOM/FC Hybrid System tools applied simultaneously to eight activity classes was validated after dividing the 389 compounds into a training set and a test set, including 259 and 130 molecules, respectively. The proper experimental activity class, among the eight possible ones, was predicted simultaneously and correctly for 81% of the test set compounds. PMID:11461760

  12. Bioavailability of dietary polyphenols: Factors contributing to their clinical application in CNS diseases.

    PubMed

    Pandareesh, M D; Mythri, R B; Srinivas Bharath, M M

    2015-10-01

    The anatomical location of the central nervous system (CNS) renders it immunologically and pharmacologically privileged due to the blood brain barrier (BBB). Although this limits the transport of unfavorable molecules to the CNS, the ensuing privilege could be disadvantageous for therapeutic compounds. Hence, the greatest challenge in the pharmacotherapy of CNS diseases is to ensure efficient brain targeting and drug delivery. Research evidences indicate that dietary polyphenols have neuroprotective potential against CNS diseases. However, their selective permeability across BBB, poor absorption, rapid metabolism and systemic elimination limit their bioavailability and therapeutic efficacy. Consequently, the beneficial effects of these orally administered agents in the CNS still remain a subject of debate. This has also limited its clinical application either as independent or adjunctive therapy. Improving the in vivo bioavailability by novel methods could improve the therapeutic feasibility of polyphenols and assist in evolving novel drugs and their derivatives with improved efficacy in vivo. Here we review the mechanistic and pharmacological issues related to the bioavailability of polyphenols with therapeutic implications for CNS diseases. We surmise that improving the bioavailability of polyphenols entails efficient in vivo transport across BBB, biochemical stability, improved half-life and persistent neuroprotection in the CNS. PMID:26163045

  13. Compartmentalized intrathecal immunoglobulin synthesis during HIV infection - a model of chronic CNS inflammation?

    PubMed

    Bonnan, Mickael; Barroso, Bruno; Demasles, Stéphanie; Krim, Elsa; Marasescu, Raluca; Miquel, Marie

    2015-08-15

    HIV infects the central nervous system (CNS) during primary infection and persists in resident macrophages. CNS infection initiates a strong local immune response that fails to control the virus but is responsible for by-stander lesions involved in neurocognitive disorders. Although highly active anti-retroviral therapy now offers an almost complete control of CNS viral proliferation, low-grade CNS inflammation persists. This review focuses on HIV-induced intrathecal immunoglobulin (Ig) synthesis. Intrathecal Ig synthesis early occurs in more than three-quarters of patients in response to viral infection of the CNS and persists throughout the course of the disease. Viral antigens are targeted but this specific response accounts for <5% of the whole intrathecal synthesis. Although the nature and mechanisms leading to non-specific synthesis are unknown, this prominent proportion is comparable to that observed in various CNS viral infections. Cerebrospinal fluid-floating antibody-secreting cells account for a minority of the whole synthesis, which mainly takes place in perivascular inflammatory infiltrates of the CNS parenchyma. B-cell traffic and lineage across the blood-brain-barrier have not yet been described. We review common technical pitfalls and update the pending questions in the field. Moreover, since HIV infection is associated with an intrathecal chronic oligoclonal (and mostly non-specific) Ig synthesis and associates with low-grade axonal lesions, this could be an interesting model of the chronic intrathecal synthesis occurring during multiple sclerosis. PMID:26198917

  14. Electroacupuncture Reduces Weight Gain Induced by Rosiglitazone through PPARγ and Leptin Receptor in CNS.

    PubMed

    Jing, Xinyue; Ou, Chen; Chen, Hui; Wang, Tianlin; Xu, Bin; Lu, Shengfeng; Zhu, Bing-Mei

    2016-01-01

    We investigate the effect of electroacupuncture (EA) on protecting the weight gain side effect of rosiglitazone (RSG) in type 2 diabetes mellitus (T2DM) rats and its possible mechanism in central nervous system (CNS). Our study showed that RSG (5 mg/kg) significantly increased the body weight and food intake of the T2DM rats. After six-week treatment with RSG combined with EA, body weight, food intake, and the ratio of IWAT to body weight decreased significantly, whereas the ratio of BAT to body weight increased markedly. HE staining indicated that the T2DM-RSG rats had increased size of adipocytes in their IWAT, but EA treatment reduced the size of adipocytes. EA effectively reduced the lipid contents without affecting the antidiabetic effect of RSG. Furthermore, we noticed that the expression of PPARγ gene in hypothalamus was reduced by EA, while the expressions of leptin receptor and signal transducer and activator of transcription 3 (STAT3) were increased. Our results suggest that EA is an effective approach for inhibiting weight gain in T2DM rats treated by RSG. The possible mechanism might be through increased levels of leptin receptor and STAT3 and decreased PPARγ expression, by which food intake of the rats was reduced and RSG-induced weight gain was inhibited. PMID:26904147

  15. The MiRNA Journey from Theory to Practice as a CNS Biomarker

    PubMed Central

    Stoicea, Nicoleta; Du, Amy; Lakis, D. Christie; Tipton, Courtney; Arias-Morales, Carlos E.; Bergese, Sergio D.

    2016-01-01

    MicroRNAs (miRNAs), small nucleotide sequences that control gene transcription, have the potential to serve an expanded function as indicators in the diagnosis and progression of neurological disorders. Studies involving debilitating neurological diseases such as, Alzheimer's disease, multiple sclerosis, traumatic brain injuries, Parkinson's disease and CNS tumors, already provide validation for their clinical diagnostic use. These small nucleotide sequences have several features, making them favorable candidates as biomarkers, including function in multiple tissues, stability in bodily fluids, a role in pathogenesis, and the ability to be detected early in the disease course. Cerebrospinal fluid, with its cell-free environment, collection process that minimizes tissue damage, and direct contact with the brain and spinal cord, is a promising source of miRNA in the diagnosis of many neurological disorders. Despite the advantages of miRNA analysis, current analytic technology is not yet affordable as a clinically viable diagnostic tool and requires standardization. The goal of this review is to explore the prospective use of CSF miRNA as a reliable and affordable biomarker for different neurological disorders. PMID:26904099

  16. C/EBPβ and C/EBPδ transcription factors: Basic biology and roles in the CNS.

    PubMed

    Pulido-Salgado, Marta; Vidal-Taboada, Jose M; Saura, Josep

    2015-09-01

    CCAAT/enhancer binding protein (C/EBP) β and C/EBPδ are transcription factors of the basic-leucine zipper class which share phylogenetic, structural and functional features. In this review we first describe in depth their basic molecular biology which includes fascinating aspects such as the regulated use of alternative initiation codons in the C/EBPβ mRNA. The physical interactions with multiple transcription factors which greatly opens the number of potentially regulated genes or the presence of at least five different types of post-translational modifications are also remarkable molecular mechanisms that modulate C/EBPβ and C/EBPδ function. In the second part, we review the present knowledge on the localization, expression changes and physiological roles of C/EBPβ and C/EBPδ in neurons, astrocytes and microglia. We conclude that C/EBPβ and C/EBPδ share two unique features related to their role in the CNS: whereas in neurons they participate in memory formation and synaptic plasticity, in glial cells they regulate the pro-inflammatory program. Because of their role in neuroinflammation, C/EBPβ and C/EBPδ in microglia are potential targets for treatment of neurodegenerative disorders. Any strategy to reduce C/EBPβ and C/EBPδ activity in neuroinflammation needs to take into account its potential side-effects in neurons. Therefore, cell-specific treatments will be required for the successful application of this strategy. PMID:26143335

  17. The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination

    PubMed Central

    Slowik, A; Schmidt, T; Beyer, C; Amor, S; Clarner, T; Kipp, M

    2015-01-01

    BACKGROUND AND PURPOSE Modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection. EXPERIMENTAL APPROACH In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin-induced experimental demyelination. We used histological, immunohistochemical and gene expression methods. KEY RESULTS The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone-induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this compound alleviated ongoing axonal damage. CONCLUSIONS AND IMPLICATIONS We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined. PMID:25220526

  18. Electroacupuncture Reduces Weight Gain Induced by Rosiglitazone through PPARγ and Leptin Receptor in CNS

    PubMed Central

    Jing, Xinyue; Ou, Chen; Chen, Hui; Wang, Tianlin; Xu, Bin; Lu, Shengfeng; Zhu, Bing-Mei

    2016-01-01

    We investigate the effect of electroacupuncture (EA) on protecting the weight gain side effect of rosiglitazone (RSG) in type 2 diabetes mellitus (T2DM) rats and its possible mechanism in central nervous system (CNS). Our study showed that RSG (5 mg/kg) significantly increased the body weight and food intake of the T2DM rats. After six-week treatment with RSG combined with EA, body weight, food intake, and the ratio of IWAT to body weight decreased significantly, whereas the ratio of BAT to body weight increased markedly. HE staining indicated that the T2DM-RSG rats had increased size of adipocytes in their IWAT, but EA treatment reduced the size of adipocytes. EA effectively reduced the lipid contents without affecting the antidiabetic effect of RSG. Furthermore, we noticed that the expression of PPARγ gene in hypothalamus was reduced by EA, while the expressions of leptin receptor and signal transducer and activator of transcription 3 (STAT3) were increased. Our results suggest that EA is an effective approach for inhibiting weight gain in T2DM rats treated by RSG. The possible mechanism might be through increased levels of leptin receptor and STAT3 and decreased PPARγ expression, by which food intake of the rats was reduced and RSG-induced weight gain was inhibited. PMID:26904147

  19. Armies of pestilence: CNS infections as potential weapons of mass destruction.

    PubMed

    Hart, B L; Ketai, L

    2015-06-01

    Infectious agents have been investigated, developed, and used by both governments and terrorist groups as weapons of mass destruction. CNS infections, though traditionally considered less often than respiratory diseases in this scenario, may be very important. Viruses responsible for encephalitides can be highly infectious in aerosol form. CNS involvement in anthrax is ominous but should change treatment. Brucellosis, plague, Q fever, and other bacteria can uncommonly manifest with meningoencephalitis and other findings. Emerging diseases may also pose threats. We review infectious agents of particular concern for purposes of biowarfare with respect to CNS manifestations and imaging features. PMID:25477355

  20. Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE

    PubMed Central

    Clarkson, Benjamin D; Walker, Alec; Harris, Melissa; Rayasam, Aditya; Sandor, Matyas; Fabry, Zsuzsanna

    2014-01-01

    Evidence from experimental autoimmune encephalomyelitis (EAE) suggests that CNS-infiltrating dendritic cells (DCs) are crucial for restimulation of coinfiltrating T cells. Here we systematically quantified and visualized the distribution and interaction of CNS DCs and T cells during EAE. We report marked periventricular accumulation of DCs and myelin-specific T cells during EAE disease onset prior to accumulation in the spinal cord, indicating that the choroid plexus-CSF axis is a CNS entry portal. Moreover, despite emphasis on spinal cord inflammation in EAE and in correspondence with MS pathology, inflammatory lesions containing interacting DCs and T cells are present in specific brain regions. PMID:25288303

  1. A Practical Guide for Exploring Opportunities of Repurposing Drugs for CNS Diseases in Systems Biology.

    PubMed

    Mei, Hongkang; Feng, Gang; Zhu, Jason; Lin, Simon; Qiu, Yang; Wang, Yue; Xia, Tian

    2016-01-01

    Systems biology has shown its potential in facilitating pathway-focused therapy development for central nervous system (CNS) diseases. An integrated network can be utilized to explore the multiple disease mechanisms and to discover repositioning opportunities. This review covers current therapeutic gaps for CNS diseases and the role of systems biology in pharmaceutical industry. We conclude with a Multiple Level Network Modeling (MLNM) example to illustrate the great potential of systems biology for CNS diseases. The system focuses on the benefit and practical applications in pathway centric therapy and drug repositioning. PMID:26235090

  2. Acquired immune deficiency syndrome (AIDS).

    PubMed

    1987-02-01

    The International Planned Parenthood Medical Advisory Panel has developed recommendations to assist family planning associations in playing a more active role in the prevention and control of acquired immunodeficiency syndrome (AIDS). Of primary importance is an effective program of information and education aimed at communicating the following facts: AIDS is a fatal disease for which there is no cure; AIDS is spread by sexual intercourse, contaminated blood, and contaminated needles; an infected woman can transmit AIDS to her fetus during pregnancy; a monogamous sexual relationship is the surest way to avoid AIDS infection; condom use is good protection; an infected person can look and feel well, yet still be able to transmit the AIDS virus; and AIDS is not spread by ordinary contact with an infected person. Family planning associations should include information on AIDS in all existing IEC projects, as well as develop new materials. Among the target audiences for IEC activities are family planning workers, family planning clients, and the general public including youth, teachers, parents, employers, and national leaders. Special attention should be given to high-risk groups such as homosexual and bisexual men, hemophiliacs, male and female prostitutes, clients of sexually transmitted disease clinics, people with many sexual partners, illegal users of intravenous drugs, and the sexual partners of those in any of these groups. Wide promotion of condom use is a priority activity for family planning organizations. PMID:12340977

  3. Infections Acquired in the Garden.

    PubMed

    Cunha, Cheston B; Cunha, Burke A

    2015-10-01

    Gardening is a wonderful pastime, and the garden is a very peaceful place to enjoy one's vacation. However, the garden may be a treacherous place for very young or compromised hosts when one takes into account the infectious potential residing in the soil, as well as the insect vectors on plants and animals. Even normal hosts may acquire a variety of infections from the soil, animals, or animal-related insect bites. The location of the garden, its natural animal and insect inhabitants, and the characteristics of the soil play a part in determining its infectious potential. The most important factor making the garden an infectious and dangerous place is the number and interaction of animals, whether they are pets or wild, that temporarily use the garden for part of their daily activities. The clinician should always ask about garden exposure, which will help in eliminating the diagnostic possibilities for the patient. The diagnostic approach is to use epidemiological principles in concert with clinical clues, which together should suggest a reasonable list of diagnostic possibilities. Organ involvement and specific laboratory tests help further narrow the differential diagnosis and determine the specific tests necessary to make a definitive diagnosis. PMID:26542044

  4. Associative Learning Through Acquired Salience

    PubMed Central

    Treviño, Mario

    2016-01-01

    Most associative learning studies describe the salience of stimuli as a fixed learning-rate parameter. Presumptive saliency signals, however, have also been linked to motivational and attentional processes. An interesting possibility, therefore, is that discriminative stimuli could also acquire salience as they become powerful predictors of outcomes. To explore this idea, we first characterized and extracted the learning curves from mice trained with discriminative images offering varying degrees of structural similarity. Next, we fitted a linear model of associative learning coupled to a series of mathematical representations for stimulus salience. We found that the best prediction, from the set of tested models, was one in which the visual salience depended on stimulus similarity and a non-linear function of the associative strength. Therefore, these analytic results support the idea that the net salience of a stimulus depends both on the items' effective salience and the motivational state of the subject that learns about it. Moreover, this dual salience model can explain why learning about a stimulus not only depends on the effective salience during acquisition but also on the specific learning trajectory that was used to reach this state. Our mathematical description could be instrumental for understanding aberrant salience acquisition under stressful situations and in neuropsychiatric disorders like schizophrenia, obsessive-compulsive disorder, and addiction. PMID:26793078

  5. Associative Learning Through Acquired Salience.

    PubMed

    Treviño, Mario

    2015-01-01

    Most associative learning studies describe the salience of stimuli as a fixed learning-rate parameter. Presumptive saliency signals, however, have also been linked to motivational and attentional processes. An interesting possibility, therefore, is that discriminative stimuli could also acquire salience as they become powerful predictors of outcomes. To explore this idea, we first characterized and extracted the learning curves from mice trained with discriminative images offering varying degrees of structural similarity. Next, we fitted a linear model of associative learning coupled to a series of mathematical representations for stimulus salience. We found that the best prediction, from the set of tested models, was one in which the visual salience depended on stimulus similarity and a non-linear function of the associative strength. Therefore, these analytic results support the idea that the net salience of a stimulus depends both on the items' effective salience and the motivational state of the subject that learns about it. Moreover, this dual salience model can explain why learning about a stimulus not only depends on the effective salience during acquisition but also on the specific learning trajectory that was used to reach this state. Our mathematical description could be instrumental for understanding aberrant salience acquisition under stressful situations and in neuropsychiatric disorders like schizophrenia, obsessive-compulsive disorder, and addiction. PMID:26793078

  6. Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP glucuronosyltransferase 1 (UGT1) locus.

    PubMed

    Fujiwara, Ryoichi; Nguyen, Nghia; Chen, Shujuan; Tukey, Robert H

    2010-03-16

    High levels of unconjugated bilirubin (UCB) in newborn children is associated with a reduction in hepatic UDP glucuronosyltransferase (UGT) 1A1 activity that can lead to CNS toxicity, brain damage, and even death. Little is known regarding those events that lead to UCB accumulation in brain tissue, and therefore, we sought to duplicate this condition in mice. The human UGT1 locus, encoding all 9-UGT1A genes including UGT1A1, was expressed in Ugt1(-/-) mice. Because the most common clinical condition associated with jaundice in adults is Gilbert's syndrome, which is characterized by an allelic polymorphism in the UGT1A1 promoter, hyperbilirubinemia was monitored in humanized UGT1 mice that expressed either the Gilbert's UGT1A1*28 allele [Tg(UGT1(A1*28))Ugt1(-/-) mice] or the normal UGT1A1*1 allele [Tg(UGT1(A1*1))Ugt1(-/-) mice]. Adult Tg(UGT1(A1*28))Ugt1(-/-) mice expressed elevated levels of total bilirubin (TB) compared with Tg(UGT1(A1*1))Ugt1(-/-) mice, confirming that the promoter polymorphism associated with the UGT1A1*28 allele contributes to hyperbilirubinemia in mice. However, TB accumulated to near toxic levels during neonatal development, a finding that is independent of the Gilbert's UGT1A1*28 promoter polymorphism. Whereas serum TB levels eventually returned to adult levels, TB clearance in neonatal mice was not associated with hepatic UGT1A1 expression. In approximately 10% of the humanized UGT1 mice, peak TB levels culminated in seizures followed by death. UCB deposition in brain tissue and the ensuing seizures were associated with developmental milestones and can be prevented by enhancing regulation of the UGT1A1 gene in neonatal mice. PMID:20194756

  7. Safety Design and Mock-Up Tests on the Combustion of Hydrogen-Air Mixture in the Vertical CNS Channel of the CARR-CNS

    SciTech Connect

    Qingfeng Yu; Quanke Feng

    2006-07-01

    A two-phase thermo-siphon loop is applied to the Cold Neutron Source (CNS) of China Advanced Research Reactor (CARR). The moderator is liquid hydrogen. The two-phase thermo-siphon consists of the crescent-shape moderator cell, the moderator transfer tube, and the condenser. The hydrogen is supplied from the buffer tank to the condenser. The most characteristic point is that the cold helium gas is introduced into the helium sub-cooling system covering the moderator cell and then flows up through the tube covering the moderator transfer tube into the condenser. The helium sub-cooling system also reduces the void fraction of the liquid hydrogen and takes a role of the helium barrier for preventing air from intruding into the hydrogen system. We call the two-phase thermo-siphon the hydrogen cold system. The main part of this system is installed in the CNS channel made of 6061 aluminum alloy (6061A) of 6 mm in thickness, 270 mm in outer diameter and about 6 m in height. For confirming the safety of the CNS, the combustion tests were carried out using the hydrogen-air mixture under the conditions in which air is introduced into the tube at 1 atmosphere, and then hydrogen gas is supplied from the gas cylinder up to the test pressures. And maximum test pressure is 0.140 MPa Gauge (G). This condition includes the design accident of the CNS. The peak pressure due to combustion is 1.09 MPa, and the design strength of the CNS channel is 3 MPa. The safety of the CNS was thus verified even if the design basis accident occurs. The pressure distribution, the stress, and the displacement of the tube were also measured. (authors)

  8. Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome.

    PubMed

    Pohl, Daniela; Alper, Gulay; Van Haren, Keith; Kornberg, Andrew J; Lucchinetti, Claudia F; Tenembaum, Silvia; Belman, Anita L

    2016-08-30

    Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating CNS disorder with predilection to early childhood. ADEM is generally considered a monophasic disease. However, recurrent ADEM has been described and defined as multiphasic disseminated encephalomyelitis. ADEM often occurs postinfectiously, although a causal relationship has never been established. ADEM and multiple sclerosis are currently viewed as distinct entities, generally distinguishable even at disease onset. However, pathologic studies have demonstrated transitional cases of yet unclear significance. ADEM is clinically defined by acute polyfocal neurologic deficits including encephalopathy. MRI typically demonstrates reversible, ill-defined white matter lesions of the brain and often also the spinal cord, along with frequent involvement of thalami and basal ganglia. CSF analysis may reveal a mild pleocytosis and elevated protein, but is generally negative for intrathecal oligoclonal immunoglobulin G synthesis. In the absence of a specific diagnostic test, ADEM is considered a diagnosis of exclusion, and ADEM mimics, especially those requiring a different treatment approach, have to be carefully ruled out. The role of biomarkers, including autoantibodies like anti-myelin oligodendrocyte glycoprotein, in the pathogenesis and diagnosis of ADEM is currently under debate. Based on the presumed autoimmune etiology of ADEM, the current treatment approach consists of early immunotherapy. Outcome of ADEM in pediatric patients is generally favorable, but cognitive deficits have been reported even in the absence of other neurologic sequelae. This review summarizes the current knowledge on epidemiology, pathology, clinical presentation, neuroimaging features, CSF findings, differential diagnosis, therapy, and outcome, with a focus on recent advances and controversies. PMID:27572859

  9. LRP1 expression in microglia is protective during CNS autoimmunity.

    PubMed

    Chuang, Tzu-Ying; Guo, Yong; Seki, Scott M; Rosen, Abagail M; Johanson, David M; Mandell, James W; Lucchinetti, Claudia F; Gaultier, Alban

    2016-01-01

    Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis. Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue. Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis. We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus. At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α. We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia. Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis. PMID:27400748

  10. Carbon monoxide inhalation increases microparticles causing vascular and CNS dysfunction

    SciTech Connect

    Xu, Jiajun; Yang, Ming; Kosterin, Paul; Salzberg, Brian M.; Milovanova, Tatyana N.; Bhopale, Veena M.; Thom, Stephen R.

    2013-12-01

    We hypothesized that circulating microparticles (MPs) play a role in pro-inflammatory effects associated with carbon monoxide (CO) inhalation. Mice exposed for 1 h to 100 ppm CO or more exhibit increases in circulating MPs derived from a variety of vascular cells as well as neutrophil activation. Tissue injury was quantified as 2000 kDa dextran leakage from vessels and as neutrophil sequestration in the brain and skeletal muscle; and central nervous system nerve dysfunction was documented as broadening of the neurohypophysial action potential (AP). Indices of injury occurred following exposures to 1000 ppm for 1 h or to 1000 ppm for 40 min followed by 3000 ppm for 20 min. MPs were implicated in causing injuries because infusing the surfactant MP lytic agent, polyethylene glycol telomere B (PEGtB) abrogated elevations in MPs, vascular leak, neutrophil sequestration and AP prolongation. These manifestations of tissue injury also did not occur in mice lacking myeloperoxidase. Vascular leakage and AP prolongation were produced in naïve mice infused with MPs that had been obtained from CO poisoned mice, but this did not occur with MPs obtained from control mice. We conclude that CO poisoning triggers elevations of MPs that activate neutrophils which subsequently cause tissue injuries. - Highlights: • Circulating microparticles (MPs) increase in mice exposed to 100 ppm CO or more. • MPs are lysed by infusing the surfactant polyethylene glycol telomere B. • CO-induced MPs cause neutrophil activation, vascular leak and CNS dysfunction. • Similar tissue injuries do not arise with MPs obtained from air-exposed, control mice.

  11. Clinicopathological associations of acquired erythroblastopenia

    PubMed Central

    Gunes, Gursel; Malkan, Umit Yavuz; Yasar, Hatime Arzu; Eliacik, Eylem; Haznedaroglu, Ibrahim Celalettin; Demiroglu, Haluk; Sayinalp, Nilgun; Aksu, Salih; Etgul, Sezgin; Aslan, Tuncay; Goker, Hakan; Ozcebe, Osman Ilhami; Buyukasik, Yahya

    2015-01-01

    Introduction: Acquired erythroblastopenia (AE) is a rare clinical situation. It is characterized by the reduction of erythroid precursors in the bone marrow together with the low reticulocyte counts in the peripheral blood. Background: Main secondary causes of AE are drugs, Parvovirus B19 and other infectious reasons, lymphoid and myeloid neoplasia, autoimmune diseases, thymoma and pregnancy. The aim of this study is to assess the frequencies and clinical associations of AE via analyzing 12340 bone marrow samples in a retrospective manner. Material and method: Bone marrow aspirations which were obtained from patients who applied to Hacettepe University Hematology Clinic between 2002 and 2013, were analyzed retrospectively. Results: Thirty four erythroblastopenia cases were found. Patients ranged in age from 16 to 80 years with a median of 38 years. Fifteen patients were men (44%) and nineteen were women (56%). In these patients, detected causes of erythroblastopenia were MDS, idiopathic pure red cell aplasia (PRCA), parvovirus infection, post chemotherapy aplasia, plasma proliferative diseases, copper deficiency due to secondary amyloidosis, fever of unknown origin, hemophagocytic syndrome, enteric fever and legionella pneumonia. We found that between those reasons the most common causes of erythroblastopenia are MDS (17.7%) and idiopathic PRCA (17.7%). Discussion: As a result, erythroblastopenia in the bone marrow may be an early sign of MDS. In those AE cases possibility of being MDS must be kept in mind as it can be mistaken for PRCA. Conclusion: To conclude, in adults MDS without excess blast is one of the most common causes of erythroblastopenia in clinical practice and in case of erythroblastopenia the presence of MDS should be investigated. PMID:26885236

  12. Surface Sampler Arm Acquiring Sample

    NASA Technical Reports Server (NTRS)

    1976-01-01

    Operation of the surface sampler in obtaining Martian soil for Viking 2's molecular analysis experiment last Saturday (September 25) was closely monitored by one of the Lander cameras because of the precision required in trenching the small area--8 by 9 inches-surrounded by rocks. Dubbed 'Bonneville Salt Flats,' the exposure of thin crust appeared unique in contrast with surrounding materials and became a prime target for organic analysis in spite of potential hazards. Large rock in foreground is 8 inches high. At left, the sampler scoop has touched the surface, missing the rock at upper left by a comfortable 6 inches, and the backhoe has penetrated the surface about one-half inch. The scoop was then pulled back to sample the desired point and (second photo) the backhoe furrowed the surface pulling a piece of thin crust toward the spacecraft. The initial touchdown and retraction sequence was used to avoid a collision between a rock in the shadow of the arm and a plate joining the arm and scoop. The rock was cleared by 2 to 3 inches. The third picture was taken 8 minutes after the scoop touched the surface and shows that the collector head has acquired a quantity of soil. With surface sampler withdrawn (right), the foot-long trench is seen between the rocks. The trench is three inches wide and about 1 1/2 to 2 inches deep. The scoop reached to within 3 inches of the rock at far end of trench. Penetration appears to have left a cavernous opening roofed by the crust and only about one inch of undisturbed crust separates the deformed surface and the rock.

  13. From fish to man: understanding endogenous remyelination in CNS demyelinating diseases

    PubMed Central

    Dubois-Dalcq, Monique; Williams, Anna; Stadelmann, Christine; Stankoff, Bruno; Zalc, Bernard; Lubetzki, Catherine

    2008-01-01

    In the central nervous system (CNS) of man, evolutionary pressure has preserved some capability for remyelination while axonal regeneration is very limited. In contrast, two efficient programmes of regeneration exist in the adult fish CNS, neurite regrowth and remyelination. The rapidity of CNS remyelination is critical since it not only restores fast conduction of nerve impulses but also maintains axon integrity. If myelin repair fails, axons degenerate, leading to increased disability. In the human CNS demyelinating disease Multiple Sclerosis (MS), remyelination often takes place in the midst of inflammation. Here, we discuss recent studies that address the innate repair capabilities of the axon-glia unit from fish to man. We propose that expansion of this research field will help find ways to maintain or enhance spontaneous remyelination in man. PMID:18474520

  14. Immunosuppressive Mechanisms of Malignant Gliomas: Parallels at Non-CNS Sites

    PubMed Central

    Perng, Powell; Lim, Michael

    2015-01-01

    The central nervous system (CNS) possesses powerful local and global immunosuppressive capabilities that modulate unwanted inflammatory reactions in nervous tissue. These same immune-modulatory mechanisms are also co-opted by malignant brain tumors and pose a formidable challenge to brain tumor immunotherapy. Routes by which malignant gliomas coordinate immunosuppression include the mechanical and functional barriers of the CNS; immunosuppressive cytokines and catabolites; immune checkpoint molecules; tumor-infiltrating immune cells; and suppressor immune cells. The challenges to overcoming tumor-induced immunosuppression, however, are not unique to the brain, and several analogous immunosuppressive mechanisms also exist for primary tumors outside of the CNS. Ultimately, the immune responses in the CNS are linked and complementary to immune processes in the periphery, and advances in tumor immunotherapy in peripheral sites may therefore illuminate novel approaches to brain tumor immunotherapy, and vice versa. PMID:26217588

  15. In Vivo Reprogramming for CNS Repair: Regenerating Neurons from Endogenous Glial Cells.

    PubMed

    Li, Hedong; Chen, Gong

    2016-08-17

    Neuroregeneration in the CNS has proven to be difficult despite decades of research. The old dogma that CNS neurons cannot be regenerated in the adult mammalian brain has been overturned; however, endogenous adult neurogenesis appears to be insufficient for brain repair. Stem cell therapy once held promise for generating large quantities of neurons in the CNS, but immunorejection and long-term functional integration remain major hurdles. In this Perspective, we discuss the use of in vivo reprogramming as an emerging technology to regenerate functional neurons from endogenous glial cells inside the brain and spinal cord. Besides the CNS, in vivo reprogramming has been demonstrated successfully in the pancreas, heart, and liver and may be adopted in other organs. Although challenges remain for translating this technology into clinical therapies, we anticipate that in vivo reprogramming may revolutionize regenerative medicine by using a patient's own internal cells for tissue repair. PMID:27537482

  16. Performing lumbar punctures for suspected CNS infections: experience and practice of trainee doctors.

    PubMed

    Defres, Sylviane; Mayer, Josephine; Backman, Ruth; Kneen, Rachel

    2015-11-01

    Lumbar punctures are essential in the management of suspected CNS infections. However, despite clear guidelines their use can be haphazard. This survey investigated the training, knowledge and experience of UK doctors in training in relation to lumbar punctures. PMID:26551497

  17. Auto Transplant for High Risk or Relapsed Solid or CNS Tumors

    ClinicalTrials.gov

    2016-08-15

    Ewing's Family Tumors; Renal Tumors; Hepatoblastoma; Rhabdomyosarcoma; Soft Tissue Sarcoma; Primary Malignant Brain Neoplasms; Retinoblastoma; Medulloblastoma; Supra-tentorial Primative Neuro-Ectodermal Tumor (PNET); Atypical Teratoid/Rhabdoid Tumor (AT/RT); CNS Tumors; Germ Cell Tumors

  18. Glial Development: The Crossroads of Regeneration and Repair in the CNS

    PubMed Central

    Gallo, Vittorio; Deneen, Benjamin

    2014-01-01

    Given the complexities of the mammalian CNS, its regeneration is viewed as the holy grail of regenerative medicine. Extraordinary efforts have been made to understand developmental neurogenesis, with the hopes of clinically applying this knowledge. CNS regeneration also involves glia, which comprises at least 50% of the cellular constituency of the brain, and is involved in all forms of injury and disease response, recovery and regeneration. Recent developmental studies have given us unprecedented insight into the processes that regulate the generation of CNS glia. Because restorative processes often parallel those found in development, we will peer through the lens of developmental gliogenesis to gain a clearer understanding of the processes that underlie glial regeneration under pathological conditions. Specifically, this review will focus on key signaling pathways that regulate astrocyte and oligodendrocyte development, and describe how these mechanisms are reutilized in these populations during regeneration and repair after CNS injury. PMID:25033178

  19. Dealing with Danger in the CNS: The Response of the Immune System to Injury

    PubMed Central

    Gadani, Sachin P.; Walsh, James T.; Lukens, John R.; Kipnis, Jonathan

    2015-01-01

    Fighting pathogens and maintaining tissue homeostasis are prerequisites for survival. Both of these functions are upheld by the immune system, though the latter is often overlooked in the context of the CNS. The mere presence of immune cells in the CNS was long considered a hallmark of pathology, but this view has been recently challenged by studies demonstrating that immunological signaling can confer pivotal neuroprotective effects on the injured CNS. In this review we describe the temporal sequence of immunological events that follow CNS injury. Beginning with immediate changes at the injury site including death of neural cells and release of damage-associated molecular patterns (DAMPs), and progressing through innate and adaptive immune responses, we describe the cascade of inflammatory mediators and the implications of their post-injury effects. We conclude by proposing a revised interpretation of immune privilege in the brain, which takes beneficial neuro-immune communications into account. PMID:26139369

  20. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 2 2011-04-01 2011-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND... Statements of Smaller Reporting Companies § 210.8-06 Real estate operations acquired or to be acquired....

  1. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 2 2013-04-01 2013-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND...-06 Real estate operations acquired or to be acquired. If, during the period for which...

  2. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 3 2014-04-01 2014-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND...-06 Real estate operations acquired or to be acquired. If, during the period for which...

  3. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 2 2012-04-01 2012-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND...-06 Real estate operations acquired or to be acquired. If, during the period for which...

  4. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND... Statements of Smaller Reporting Companies § 210.8-06 Real estate operations acquired or to be acquired....

  5. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4

    PubMed Central

    Walsh, James T.; Hendrix, Sven; Boato, Francesco; Smirnov, Igor; Zheng, Jingjing; Lukens, John R.; Gadani, Sachin; Hechler, Daniel; Gölz, Greta; Rosenberger, Karen; Kammertöns, Thomas; Vogt, Johannes; Vogelaar, Christina; Siffrin, Volker; Radjavi, Ali; Fernandez-Castaneda, Anthony; Gaultier, Alban; Gold, Ralf; Kanneganti, Thirumala-Devi; Nitsch, Robert; Zipp, Frauke; Kipnis, Jonathan

    2015-01-01

    A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell–mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4–producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4–deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4+ T cells from wild-type mice, but not from IL-4–deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell–derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4–producing CD4+ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration. PMID:25607842

  6. Fungal infections of the CNS: treatment strategies for the immunocompromised patient.

    PubMed

    Black, Katharine E; Baden, Lindsey R

    2007-01-01

    Infections with fungi cause significant morbidity in the immunocompromised host and invasion of the CNS may lead to devastating consequences. Vulnerable individuals include those with haematological malignancies, transplant recipients, and those infected with HIV. Potential pathogens include yeasts, Aspergillus spp., other moulds of an increasing variety, and a range of dimorphic fungi, often associated with particular geographical locations. Antifungal treatments include polyenes such as amphotericin B and its lipid formulations, azoles such as fluconazole and itraconazole, and the more recent voriconazole and posaconazole. The new antifungal class of echinocandins, such as caspofungin, micafungin and anidulafungin, typically lack CNS penetration. Amphotericin B and flucytosine are used to initiate treatment for CNS yeast infections caused by Candida and Cryptococcus neoformans. Voriconazole is preferred for aspergillus, although amphotericin B, particularly in lipid formulation, is also useful. Reliable treatment data are lacking for CNS infections with most of the non-aspergillus moulds; posaconazole holds promise for the zygomycetes and perhaps some of the rarer pigmented fungi, but amphotericin B preparations are still recommended. Oral fluconazole is effective for the CNS manifestations of coccidioides, while histoplasmosis and blastomycoses typically require amphotericin B therapy. Effective treatment requires a definitive diagnosis, which is often challenging in the population at risk of CNS fungal infections. PMID:17381184

  7. Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases.

    PubMed

    Dudnik, Elizabeth; Yust-Katz, Shlomit; Nechushtan, Hovav; Goldstein, Daniel A; Zer, Alona; Flex, Dov; Siegal, Tali; Peled, Nir

    2016-08-01

    Central nervous system (CNS) metastases occur in 30% of patients with advanced non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases result in delays in systemic therapy administration and are associated with neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is approved as a second-line treatment of NSCLC. Data regarding the intracranial activity of nivolumab is lacking. We retrospectively reviewed the efficacy and safety of nivolumab in five patients with advanced NSCLC and new/progressing intracranial metastases. Intracranial response was assessed by magnetic resonance imaging (MRI) using mRECIST v. 1.1 criteria. All patients had parenchymal brain metastases; two patients had leptomeningeal carcinomatosis diagnosed according to radiological criteria. All patients were asymptomatic and did not require corticosteroids or immediate local therapy. We observed one complete and one partial response in the brain. Stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved in one additional patient. Two patients progressed in the CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still ongoing at the time of the report (24+ and 28+ weeks since start of treatment). Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS metastases-related grade≥3 adverse events were observed. Nivolumab might have intracranial activity and favorable safety profile in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity warrants further evaluation. PMID:27393516

  8. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND

    PubMed Central

    Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.

    2013-01-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

  9. Chondroitin sulfate glycosaminoglycans for CNS homeostasis-implications for material design.

    PubMed

    Karumbaiah, Lohitash; Saxena, Tarun; Betancur, Martha; Bellamkonda, Ravi V

    2014-01-01

    Chondroitin sulfate proteoglycans (CSPGs) are complex biomolecules that are known to facilitate patterning of axonal direction and cell migration during the early growth and development phase of the mammalian central nervous system (CNS). In adults, they continue to control neuronal plasticity as major constituents of the "peri-neuronal nets" (PNNs) that surround adult CNS neurons. CSPGs are also barrier-forming molecules that are selectively upregulated by invading reactive astroglia after injury to the CNS, and are responsible for the active repulsion of regenerating neurons post-injury. Recent evidence however suggests that the diverse sulfated glycosaminoglycan (GAG) side chains attached to CSPGs are key components that play paradoxical roles in influencing nerve regeneration post-injury to the CNS. Sulfated GAG repeats attached to the CSPG core protein help mediate cell migration, neuritogenesis, axonal pathfinding, and axonal repulsion by directly trapping and presenting a whole host of growth factors to cells locally, or by binding to specific membrane bound proteins on the cell surface to influence cellular function. In this review, we will present the current gamut of interventional strategies used to bridge CNS deficits, and discuss the potential advantages of using sulfated GAG based biomaterials to facilitate the repair and regeneration of the injured CNS. PMID:25139544

  10. Doxycycline as an inhibitor of p-glycoprotein in the alpaca for the purpose of maintaining avermectins in the CNS during treatment for parelaphostrongylosis.

    PubMed

    Agbedanu, Prince N; Anderson, Kristi L; Brewer, Matthew T; Carlson, Steve A

    2015-09-15

    Meningeal worms (Parelaphostrongylus tenuis) are a common malady of alpacas, often refractory to conventional treatments. Ivermectin is a very effective anthelmintic used against a variety of parasites but this drug is not consistently effective against alpaca meningeal worms once the parasite has gained access to the CNS, even if used in a protracted treatment protocol. Ivermectin is not effective against clinical cases of P. tenuis, raising the possibility that the drug is not sustained at therapeutic concentrations in the central nervous system (CNS). A specific protein (designated as p-glycoprotein (PGP)) effluxes ivermectin from the brain at the blood-brain barrier, thus hampering the maintenance of therapeutic concentrations of the drug in the CNS. Minocycline is a synthetic tetracycline antibiotic with an excellent safety profile in all animals tested to date. Minocycline has three unique characteristics that could be useful for treating meningeal worms in conjunction with ivermectin. First, minocycline is an inhibitor of PGP at the blood-brain barrier and this inhibition could maintain effective concentrations of ivermectin in the brain and meninges. Second, minocycline protects neurons in vivo through a number of different mechanisms and this neuroprotection could alleviate the potential untoward neurologic effects of meningeal worms. Third, minocycline is a highly lipid-soluble drug, thus facilitating efficient brain penetration. We thus hypothesized that minocycline will maintain ivermectin, or a related avermectin approved in ruminants (abamectin, doramectin, or eprinomectin), in the alpaca CNS. To test this hypothesis, we cloned the gene encoding the alpaca PGP, expressed the alpaca PGP in a heterologous expression system involving MDCK cells, and measured the ability of minocycline to inhibit the efflux of avermectins from the MDCK cells; doxycycline was used as a putative negative control (based on studies in other species). Our in vitro studies

  11. Acquired tracheoesophageal fistula in infancy and childhood.

    PubMed

    Szold, A; Udassin, R; Seror, D; Mogle, P; Godfrey, S

    1991-06-01

    Acquired tracheoesophageal fistula (TEF) is a rare entity in the pediatric age group. We report two pediatric patients with acquired TEF caused by shells of pistachio nuts. In both patients the primary operation did not resolve the problem and a second intervention for recurrent fistula was needed. The special nature of acquired TEF, particularly the one described herein, requires delayed surgical intervention and meticulous separation of the respiratory and alimentary tracts by an intercostal muscle flap. PMID:1941455

  12. Acquired stuttering due to recurrent anaplastic astrocytoma

    PubMed Central

    Peters, Katherine B; Turner, Scott

    2013-01-01

    Acquired (neurogenic) stuttering is a rare phenomenon seen after cerebral infarction or brain injury. Aetiology of this symptom is unclear, but recent evidence supports that it is a disturbance in the left hemispheric neural network involving the interplay between the cortex and basal ganglia. We present the case of a patient who develops acquired stuttering after a recurrence of a right temporoparietal anaplastic astrocytoma (WHO grade III). We also review other cases of acquired stuttering and known anatomical correlates. PMID:24252834

  13. Inducible and Acquired Clarithromycin Resistance in the Mycobacterium abscessus Complex

    PubMed Central

    Rubio, Marc; March, Francesca; Garrigó, Montserrat; Moreno, Carmen; Español, Montserrat; Coll, Pere

    2015-01-01

    Purpose Clarithromycin was considered the cornerstone for the treatment of Mycobacterium abscessus complex infections. Genetic resistance mechanisms have been described and many experts propose amikacin as an alternative. Nevertheless, clarithromycin has several advantages; therefore, it is necessary to identify the non-functional erm(41) allele to determine the most suitable treatment. The aims of this study were to characterize the molecular mechanisms of clarithromycin resistance in a collection of Mycobacterium abscessus complex isolates and to verify the relationship between these mechanisms and the antibiogram. Materials and Methods Clinical isolates of M. abscessus complex (n = 22) from 16 patients were identified using four housekeeping genes (rpoB, secA1, sodA and hsp65), and their genetic resistance was characterized by studying erm(41) and rrl genes. Nine strains were recovered from the clinical isolates and subjected to E-test and microdilution clarithromycin susceptibility tests, with readings at 3, 7 and 14 days. Results We classified 11/16 (68.8%) M. abscessus subsp. abscessus, 4/16 (25.0%) M. abscessus subsp. bolletii, and 1/16 (6.3%) M. abscessus subsp. massiliense. T28 erm(41) allele was observed in 8 Mycobacterium abscessus subps. abscessus and 3 Mycobacterium abscessus subsp. bolletii. One strain of M. abscessus subsp. bolletii had an erm(41) gene truncated and was susceptible to clarithromycin. No mutations were observed in rrl gene first isolates. In three patients, follow-up of initial rrl wild-type strains showed acquired resistance. Conclusions Most clinical isolates of M. abscessus complex had inducible resistance to clarithromycin and total absence of constitutive resistance. Our findings showed that the acquisition of resistance mutations in rrl gene was associated with functional and non-functional erm(41) gene. Caution is needed when using erm(41) sequencing alone to identify M. abscessus subspecies. This study reports an acquired

  14. Physiology of the intrathecal bolus: the leptomeningeal route for macromolecule and particle delivery to CNS

    PubMed Central

    Belov, Vasily V.; Gannon, Kimberley S.

    2013-01-01

    Presently, there are no effective treatments for several diseases involving the CNS, which is protected by the blood-brain, blood-CSF and blood-arachnoid barriers. Traversing any of these barriers is difficult, especially for macromolecular drugs and particulates. However, there is significant experimental evidence that large molecules can be delivered to the CNS through the cerebro-spinal fluid (CSF). The flux of the interstitial fluid in the CNS parenchyma, as well as the macro flux of CSF in the leptomeningeal space, are believed to be generally opposite to the desirable direction of CNS-targeted drug delivery. On the other hand, the available data suggest that the layer of pia mater lining the CNS surface is not continuous, and the continuity of the leptomeningeal space (LMS) with the perivascular spaces penetrating into the parenchyma provides an unexplored avenue for drug transport deep into the brain via CSF. The published data generally do not support the view that macromolecule transport from the LMS to CNS is hindered by the interstitial and CSF fluxes. The data strongly suggest that leptomeningeal transport depends on the location and volume of the administered bolus and consists of four processes: (i) pulsation-assisted convectional transport of the solutes with CSF, (ii) active “pumping” of CSF into the periarterial spaces, (iii) solute transport from the latter to and within the parenchyma, and (iv) neuronal uptake and axonal transport. The final outcome will depend on the drug molecule behavior in each of these processes, which have not been studied systematically. The data available to date suggest that many macromolecules and nanoparticles can be delivered to CNS in biologically significant amounts (>1% of the administered dose); mechanistic investigation of macromolecule and particle behavior in CSF may result in a significantly more efficient leptomeningeal drug delivery than previously thought. PMID:23316936

  15. Identification of Ind transcription activation and repression domains required for dorsoventral patterning of the CNS.

    PubMed

    Von Ohlen, Tonia L; Moses, Cade

    2009-07-01

    Specification of cell fates across the dorsoventral axis of the central nervous system in Drosophila involves the subdivision of the neuroectoderm into three domains that give rise to three columns of neural precursor cells called neuroblasts. Ventral nervous system defective (Vnd), intermediate neuroblasts defective (Ind) and muscle segment homeobox (Msh) are expressed in the three columns from ventral to dorsal, respectively. The products of these genes play multiple important roles in formation and specification of the embryonic nervous system. Ind, for example, is known to play roles in two important processes. First, Ind is essential for formation of neuroblasts conjunction with SoxB class transcription factors. Sox class transcription factors are known to specify neural stem cells in vertebrates. Second, Ind plays an important role in patterning the CNS in conjunction with, vnd and msh, which is also similar to how vertebrates pattern their neural tube. This work focuses two important aspects of Ind function. First, we used multiple approaches to identify and characterize specific domains within the protein that confer repressor or activator ability. Currently, little is known about the presence of activation or repression domains within Ind. Here, we show that transcriptional repression by Ind requires multiple conserved domains within the protein, and that Ind has a transcriptional activation domain. Specifically, we have identified a novel domain, the Pst domain, that has transcriptional repression ability and appears to act independent of interaction with the co-repressor Groucho. This domain is highly conserved among insect species, but is not found in vertebrate Gsh class homeodomain proteins. Second, we show that Ind can and does repress vnd expression, but does so in a stage specific manner. We conclude from this that the function of Ind in regulating vnd expression is one of refinement and maintenance of the dorsal border. PMID:19348939

  16. Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation

    PubMed Central

    Kumar, Suresh M.; Liu, Shujing; Lu, Hezhe; Zhang, Hongtao; Zhang, Paul J.; Gimotty, Phyllis A.; Guerra, Matthew; Guo, Wei; Xu, Xiaowei

    2012-01-01

    There is enormous interest to target cancer stem cells (CSCs) for clinical treatment because these cells are highly tumorigenic and resistant to chemotherapy. Oct4 is expressed by CSC-like cells in different types of cancer. However, function of Oct4 in tumor cells is unclear. In this study, we showed that expression of Oct4 gene or transmembrane delivery of Oct4 protein promoted dedifferentiation of melanoma cells to CSC-like cells. The dedifferentiated melanoma cells showed significantly decreased expression of melanocytic markers and acquired the ability to form tumor spheroids. They showed markedly increased resistance to chemotherapeutic agents and hypoxic injury. In the subcutaneous xenograft and tail vein injection assays, these cells had significantly increased tumorigenic capacity. The dedifferentiated melanoma cells acquired features associated with CSCs such as multipotent differentiation capacity and expression of melanoma CSC markers such as ABCB5 and CD271. Mechanistically, Oct4 induced dedifferentiation was associated with increased expression of endogenous Oct4, Nanog and Klf4, and global gene expression changes that enriched for transcription factors. RNAi mediated knockdown of Oct4 in dedifferentiated cells led to diminished CSC phenotypes. Oct4 expression in melanoma was regulated by hypoxia and its expression was detected in a subpopulation of melanoma cells in clinical samples. Our data indicate that Oct4 is a positive regulator of tumor dedifferentiation. The results suggest that CSC phenotype is dynamic and may be acquired through dedifferentiation. Oct4 mediated tumor cell dedifferentiation may play an important role during tumor progression. PMID:22286766

  17. Acquired Surface Dyslexia: The Evidence from Hebrew.

    ERIC Educational Resources Information Center

    Birnboim, Smadar

    1995-01-01

    Investigates the symptoms of acquired surface dyslexia in Hebrew. Four acquired surface dyslexic adults were compared with eight normal second graders in terms of reading strategy. Homophones and homographs were a major source of difficulty for native Hebrew surface dyslexic readers; the normal second graders used a non-lexical strategy. (45…

  18. Acquiring and Managing Electronic Journals. ERIC Digest.

    ERIC Educational Resources Information Center

    Curtis, Donnelyn; Yue, Paoshan

    Electronic journals are both a blessing and a curse for libraries. To be meaningful in the current information environment--to meet users' ever-increasing demands--libraries must acquire as many appropriate full text resources as possible, as quickly as possible, and make them easy to use. This Digest provides tips for acquiring and providing…

  19. Acquired Zinc Deficiency in an Adult Female

    PubMed Central

    Saritha, Mohanan; Gupta, Divya; Chandrashekar, Laxmisha; Thappa, Devinder M; Rajesh, Nachiappa G

    2012-01-01

    Acrodermatitis enteropathica is an autosomal recessive inherited disorder of zinc absorption. Acquired cases are reported occasionally in patients with eating disorders or Crohn's disease. We report a 24-year-old housewife with acquired isolated severe zinc deficiency with no other comorbidities to highlight the rare occurrence of isolated nutritional zinc deficiency in an otherwise normal patient. PMID:23248371

  20. Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy.

    PubMed

    Doerr, Jonas; Böckenhoff, Annika; Ewald, Benjamin; Ladewig, Julia; Eckhardt, Matthias; Gieselmann, Volkmar; Matzner, Ulrich; Brüstle, Oliver; Koch, Philipp

    2015-09-01

    Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder resulting from a functional deficiency of arylsulfatase A (ARSA), an enzyme that catalyzes desulfation of 3-O-sulfogalactosylceramide (sulfatide). Lack of active ARSA leads to the accumulation of sulfatide in oligodendrocytes, Schwann cells and some neurons and triggers progressive demyelination, the neuropathological hallmark of MLD. Several therapeutic approaches have been explored, including enzyme replacement, autologous hematopoietic stem cell-based gene therapy, intracerebral gene therapy or cell-based gene delivery into the central nervous system (CNS). However, long-term treatment of the blood-brain-barrier protected CNS remains challenging. Here we used MLD patient-derived induced pluripotent stem cells (iPSCs) to generate long-term self-renewing neuroepithelial stem cells and astroglial progenitors for cell-based ARSA replacement. Following transplantation of ARSA-overexpressing precursors into ARSA-deficient mice we observed a significant reduction of sulfatide storage up to a distance of 300 µm from grafted cells. Our data indicate that neural precursors generated via reprogramming from MLD patients can be engineered to ameliorate sulfatide accumulation and may thus serve as autologous cell-based vehicle for continuous ARSA supply in MLD-affected brain tissue. PMID:26061647

  1. Expanding the spectrum of phenotypes associated with germline PIGA mutations: a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities.

    PubMed

    van der Crabben, Saskia N; Harakalova, Magdalena; Brilstra, Eva H; van Berkestijn, Frédérique M C; Hofstede, Floris C; van Vught, Adrianus J; Cuppen, Edwin; Kloosterman, Wigard; Ploos van Amstel, Hans Kristian; van Haaften, Gijs; van Haelst, Mieke M

    2014-01-01

    Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family. PMID:24259184

  2. Acquired hemophilia masked by warfarin therapy.

    PubMed

    Kantor, R; Mayan, H; Puritz, L; Varon, D; Farfel, Z

    2000-03-01

    People without hemophilia but with autoantibodies specifically directed against the procoagulant activity of factor VIII are known to have acquired hemophilia. The bleeding diathesis in these patients is often severe and life-threatening. The definite laboratory diagnosis of this disorder includes demonstration of low factor VIII levels in plasma with a high titer of factor VIII inhibitors, but the initial suspicion for its presence should rise in view of a prolonged partial thromboblastin time (PTT) and a normal prothrombin time associated with an acquired bleeding disorder. Oral anticoagulant treatment is known to prolong PTT as well, and the merger of these 2 situations may cause delayed diagnosis of acquired hemophilia with devastating consequences. We describe here the first reported case of acquired hemophilia diagnosed in a patient treated with warfarin. In such patients prolonged PTT may be ascribed to warfarin therapy rather than to acquired hemophilia, thus causing a dangerous delay in diagnosis. PMID:10746834

  3. Targets for Combating the Evolution of Acquired Antibiotic Resistance.

    PubMed

    Culyba, Matthew J; Mo, Charlie Y; Kohli, Rahul M

    2015-06-16

    Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal. PMID:26016604

  4. Targets for Combating the Evolution of Acquired Antibiotic Resistance

    PubMed Central

    2015-01-01

    Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal. PMID:26016604

  5. Aberrant dendritic excitability: a common pathophysiology in CNS disorders affecting memory?

    PubMed Central

    Nestor, Michael W.; Hoffman, Dax A.

    2012-01-01

    Discovering the etiology of pathophysiologies and aberrant behavior in many central nervous system (CNS) disorders has proven elusive because susceptibility to these diseases can be a product of multiple factors such as genetics, epigenetics, and environment. Advances in molecular biology and wide-scale genomics have shown that a large heterogeneity of genetic mutations are potentially responsible for the neuronal pathologies and dysfunctional behaviors seen in CNS disorders. (Need to distinguish between pure genetic forms which are rare, and what most people get which is probable combination of genetic susceptibility and environmental insults). Despite this seemingly complex array of genetic and physiological factors, many disorders of the CNS converge on common dysfunctions in memory. In this review, we propose that mechanisms underlying the development of many CNS diseases may share an underlying cause involving abnormal dendritic integration of synaptic signals. Through understanding the relationship between molecular genetics and dendritic computation, future research may uncover important links between neuronal physiology at the cellular level and higher-order circuit and network abnormalities observed in CNS diseases, and their subsequent affect on memory. PMID:22528602

  6. Influenza Vaccine-Induced CNS Demyelination in a 50-Year-Old Male

    PubMed Central

    Sacheli, Aaron; Bauer, Raymond

    2014-01-01

    Patient: Male, 50 Final Diagnosis: Acute post-vaccination CNS demyelinating disorder Symptoms: Blurred vision • hemiparesis • hemiplegia • hypertonia • itching • paresthesia Medication: — Clinical Procedure: MRI Specialty: Neurology Objective: Rare disease Background: There are several categories of primary inflammatory demyelinating disorders, which comprise clinically similar neurologic sequelae. Of interest, clinically isolated syndrome (CIS) and acute disseminated encephalomyelitis (ADEM) are 2 demyelinating conditions of the central nervous system (CNS), whose clinical similarity pose a significant challenge to definitive diagnosis. Yet, both remain important clinical considerations in patients with neurologic signs and symptoms in the context of recent vaccination. Case Report: We report a case of a 50-year-old Caucasian male with a course of progressive, focal, neurologic deficits within 24 h after receiving the influenza vaccine. Subsequent work-up revealed the possibility of an acute central nervous system (CNS) demyelinating episode secondary to the influenza vaccine, best described as either CIS or ADEM. Conclusions: Case reports of CNS demyelination following vaccinations have been previously noted, most often occurring in the context of recent influenza vaccination. This report serves to document a case of CNS demyelination occurring 24 h after influenza vaccination in a middle-aged patient, and will describe some salient features regarding the differential diagnosis of CIS and ADEM, as well as their potential management. PMID:25175754

  7. Immune privilege of the CNS is not the consequence of limited antigen sampling

    NASA Astrophysics Data System (ADS)

    Harris, Melissa G.; Hulseberg, Paul; Ling, Changying; Karman, Jozsef; Clarkson, Benjamin D.; Harding, Jeffrey S.; Zhang, Mengxue; Sandor, Adam; Christensen, Kelsey; Nagy, Andras; Sandor, Matyas; Fabry, Zsuzsanna

    2014-03-01

    Central nervous system (CNS) immune privilege is complex, and it is still not understood how CNS antigens are sampled by the peripheral immune system under steady state conditions. To compare antigen sampling from immune-privileged or nonprivileged tissues, we created transgenic mice with oligodendrocyte or gut epithelial cell expression of an EGFP-tagged fusion protein containing ovalbumin (OVA) antigenic peptides and tested peripheral anti-OVA peptide-specific sentinel OT-I and OT-II T cell activation. We report that oligodendrocyte or gut antigens are sampled similarly, as determined by comparable levels of OT-I T cell activation. However, activated T cells do not access the CNS under steady state conditions. These data show that afferent immunity is normally intact as there is no barrier at the antigen sampling level, but that efferent immunity is restricted. To understand how this one-sided surveillance contributes to CNS immune privilege will help us define mechanisms of CNS autoimmune disease initiation.

  8. The microglial ATP-gated ion channel P2X7 as a CNS drug target.

    PubMed

    Bhattacharya, Anindya; Biber, Knut

    2016-10-01

    Based on promising preclinical evidence, microglial P2X7 has increasingly being recognized as a target for therapeutic intervention in neurological and psychiatric diseases. However, despite this knowledge no P2X7-related drug has yet entered clinical trials with respect to CNS diseases. We here discuss the current literature on P2X7 being a drug target and identify unsolved issues and still open questions that have hampered the development of P2X7 dependent therapeutic approaches for CNS diseases. It is concluded here that the lack of brain penetrating P2X7 antagonists is a major obstacle in the field and that central P2X7 is a yet untested clinical drug target. In the CNS, microglial P2X7 activation causes neuroinflammation, which in turn plays a role in various CNS disorders. This has resulted in a surge of brain penetrant P2X7 antagonists. P2X7 is a viable, clinically untested CNS drug target. GLIA 2016;64:1772-1787. PMID:27219534

  9. Matrine protects neuro-axon from CNS inflammation-induced injury.

    PubMed

    Kan, Quan-Cheng; Lv, Peng; Zhang, Xiao-Jian; Xu, Yu-Ming; Zhang, Guang-Xian; Zhu, Lin

    2015-02-01

    Neuro-axonal injury in the central nervous system (CNS) is one of the major pathological hallmarks of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has recently been shown to effectively suppress EAE through an anti-inflammatory mechanism. However, whether MAT can also protect myelin/axons from damage is not known. In the present study we show that, while untreated rats developed severe clinical disease, CNS inflammatory demyelination, and axonal damage, these clinical and pathological signs were significantly reduced by MAT treatment. Consistently, MAT treatment reduced the concentration of myelin basic protein in serum and downregulated expression of β-amyloid (Aβ) and B-site APP cleaving enzyme 1 (BACE-1) in the CNS. Further, the CNS of MAT-treated rats exhibited increased expression of brain-derived neurotrophic factor (BDNF), an important factor for neuronal survival and axonal growth. Together, these results demonstrate that MAT effectively prevented neuro-axonal injury, which can likely be attributed to inhibiting risk factors such as BACE-1 and upregulating neuroprotective factors such as BDNF. We conclude that this novel natural reagent, MAT, which effectively protects neuro-axons from CNS inflammation-induced damage, could be a potential candidate for the treatment of neurodegenerative diseases such as MS. PMID:25576296

  10. Immune privilege of the CNS is not the consequence of limited antigen sampling

    PubMed Central

    Harris, Melissa G.; Hulseberg, Paul; Ling, Changying; Karman, Jozsef; Clarkson, Benjamin D.; Harding, Jeffrey S.; Zhang, Mengxue; Sandor, Adam; Christensen, Kelsey; Nagy, Andras; Sandor, Matyas; Fabry, Zsuzsanna

    2014-01-01

    Central nervous system (CNS) immune privilege is complex, and it is still not understood how CNS antigens are sampled by the peripheral immune system under steady state conditions. To compare antigen sampling from immune-privileged or nonprivileged tissues, we created transgenic mice with oligodendrocyte or gut epithelial cell expression of an EGFP-tagged fusion protein containing ovalbumin (OVA) antigenic peptides and tested peripheral anti-OVA peptide-specific sentinel OT-I and OT-II T cell activation. We report that oligodendrocyte or gut antigens are sampled similarly, as determined by comparable levels of OT-I T cell activation. However, activated T cells do not access the CNS under steady state conditions. These data show that afferent immunity is normally intact as there is no barrier at the antigen sampling level, but that efferent immunity is restricted. To understand how this one-sided surveillance contributes to CNS immune privilege will help us define mechanisms of CNS autoimmune disease initiation. PMID:24651727

  11. Immune privilege of the CNS is not the consequence of limited antigen sampling.

    PubMed

    Harris, Melissa G; Hulseberg, Paul; Ling, Changying; Karman, Jozsef; Clarkson, Benjamin D; Harding, Jeffrey S; Zhang, Mengxue; Sandor, Adam; Christensen, Kelsey; Nagy, Andras; Sandor, Matyas; Fabry, Zsuzsanna

    2014-01-01

    Central nervous system (CNS) immune privilege is complex, and it is still not understood how CNS antigens are sampled by the peripheral immune system under steady state conditions. To compare antigen sampling from immune-privileged or nonprivileged tissues, we created transgenic mice with oligodendrocyte or gut epithelial cell expression of an EGFP-tagged fusion protein containing ovalbumin (OVA) antigenic peptides and tested peripheral anti-OVA peptide-specific sentinel OT-I and OT-II T cell activation. We report that oligodendrocyte or gut antigens are sampled similarly, as determined by comparable levels of OT-I T cell activation. However, activated T cells do not access the CNS under steady state conditions. These data show that afferent immunity is normally intact as there is no barrier at the antigen sampling level, but that efferent immunity is restricted. To understand how this one-sided surveillance contributes to CNS immune privilege will help us define mechanisms of CNS autoimmune disease initiation. PMID:24651727

  12. Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease.

    PubMed

    Greenhalgh, Andrew D; Passos Dos Santos, Rosmarini; Zarruk, Juan Guillermo; Salmon, Christopher K; Kroner, Antje; David, Samuel

    2016-08-01

    Resident microglia and infiltrating myeloid cells play important roles in the onset, propagation, and resolution of inflammation in central nervous system (CNS) injury and disease. Identifying cell type-specific mechanisms will help to appropriately target interventions for tissue repair. Arginase-1 (Arg-1) is a well characterised modulator of tissue repair and its expression correlates with recovery after CNS injury. Here we assessed the cellular localisation of Arg-1 in two models of CNS damage. Using microglia specific antibodies, P2ry12 and Fc receptor-like S (FCRLS), we show the LysM-EGFP reporter mouse is an excellent model to distinguish infiltrating myeloid cells from resident microglia. We show that Arg-1 is expressed exclusively in infiltrating myeloid cells but not microglia in models of spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE). Our in vitro studies suggest that factors in the CNS environment prevent expression of Arg-1 in microglia in vivo. This work suggests different functional roles for these cells in CNS injury and repair and shows that such repair pathways can be switched on in infiltrating myeloid cells in pro-inflammatory environments. PMID:27126514

  13. Expanded CD8 T-cell sharing between periphery and CNS in multiple sclerosis

    PubMed Central

    Salou, Marion; Garcia, Alexandra; Michel, Laure; Gainche-Salmon, Anne; Loussouarn, Delphine; Nicol, Bryan; Guillot, Flora; Hulin, Philippe; Nedellec, Steven; Baron, Daniel; Ramstein, Gérard; Soulillou, Jean-Paul; Brouard, Sophie; Nicot, Arnaud B; Degauque, Nicolas; Laplaud, David A

    2015-01-01

    Objective In multiple sclerosis (MS), central nervous system (CNS), cerebrospinal fluid (CSF), and blood display TCR clonal expansions of CD8+ T cells. These clones have been assumed – but never demonstrated – to be similar in the three compartments. Addressing this key question is essential to infer the implication of peripheral clonally expanded CD8+ T cells in the disease. Methods For the first time, TCR Vβ repertoire from paired blood (purified CD8+ and CD4+ T cells), CSF and CNS (22 lesions, various inflammatory and demyelination statuses) samples from three MS patients was studied using complementary determining region 3 (CDR3) spectratyping and high-throughput sequencing. In parallel, blood and CNS clonally expanded CD8+ T cells were characterized by fluorescent staining. Results TCR Vβ repertoire analysis revealed strong sharing of predominant T-cell clones between CNS lesions, CSF, and blood CD8+ T cells. In parallel, we showed that blood oligoclonal CD8+ T cells exhibit characteristics of pathogenic cells, as they displayed a bias toward a memory phenotype in MS patients, with increased expression of CCR5, CD11a and Granzyme B (GZM-B) compared to non oligoclonal counterparts. CNS-infiltrating T cells were mainly CD8 expressing CD11a and GZM-B. Interpretation This study highlights the predominant implication of CD8+ T cells in MS pathophysiology and demonstrates that potentially aggressive CD8+ T cells can be easily identified and characterized from blood and CSF samples. PMID:26125037

  14. Coagulase-negative staphylococci (CNS) as an aetiological factor of mastitis in cows.

    PubMed

    Bochniarz, M; Wawron, W; Szczubiał, M

    2013-01-01

    The aim of the present study was to determine the proportions of individual coagulase-negative Staphylococcus species in clinical and subclinical mastitis. The material consisted of 100 CNS isolates obtained from 223 milk samples collected from cows with clinical and subclinical mastitis. Coagulase-negative staphylococci constituted 44.8% of all isolated microorganisms. CNS were isolated from the mammary gland secretions of 86 cows from farms in the Lublin region (Poland). Clinical mastitis was found in 20 whereas subclinical mastitis in 66 study cows (23.3% and 76.7%, respectively). The symptoms of clinical mastitis were mild. The clinical forms of mastitis concerned mainly the first or second lactation. Subclinical mastitis was most commonly observed during the second lactation. Four CNS species (S. xylosus, S. chromogenes, S. haemolyticus and S. sciuri) were isolated from clinical and subclinical mastitis. S. xylosus was the commonest CNS species isolated from cows with clinical mastitis whereas S. chromogenes was the most prevalent one in subclinical mastitis cases. The three CNS species (S. warneri, S. hominis and S. saprophyticus) caused only subclinical mastitis. PMID:24195283

  15. Truncated N-terminal mutants of SV40 large T antigen as minimal immortalizing agents for CNS cells

    PubMed Central

    Freed, William J.; Zhang, Peisu; Sanchez, Joseph F.; Dillon-Carter, Ora; Coggiano, Mark; Errico, Stacie L.; Lewis, Brian D.; Truckenmiller, Mary Ellen

    2007-01-01

    Immortalized central nervous system (CNS) cell lines are useful as in vitro models for innumerable purposes such as elucidating biochemical pathways, studies of effects of drugs, and ultimately, such cells may also be useful for neural transplantation. The SV40 large T (LT) oncoprotein, commonly used for immortalization, interacts with several cell cycle regulatory factors, including binding and inactivating p53 and retinoblastoma family cell-cycle regulators. In an attempt to define the minimal requirements of SV40 T antigen for immortalizing cells of CNS origin, we constructed T155c, encoding the N-terminal 155 amino acids of LT. The p53 binding region is known to reside in the C-terminal region of LT. An additional series of mutants was produced to further narrow the molecular targets for immortalization, and plasmid vectors were constructed for each. In a p53 temperature sensitive cell line model, T64-7B, expression of T155c and all constructs having mutations outside of the first 82 amino acids were capable of overriding cell-cycle block at the non-permissive growth temperature. Several cell lines were produced from fetal rat mesencephalic and cerebral cortical cultures using the T155c construct. The E107K construct contained a mutation in the Rb binding region, but was nonetheless capable of overcoming cell cycle block in T64-7B cell and immortalizing primary cultured cells. Cells immortalized with T155c were often highly dependent on the presence of bFGF for growth. Telomerase activity, telomere length, growth rates, and integrity of the p53 gene in cells immortalized with T155c did not change over 100 population doublings in culture, indicating that cells immortalized with T155c were generally stable during long periods of continuous culture. PMID:15629761

  16. Aromatherapy and the central nerve system (CNS): therapeutic mechanism and its associated genes.

    PubMed

    Lv, Xiao Nan; Liu, Zhu Jun; Zhang, Huan Jing; Tzeng, Chi Meng

    2013-07-01

    Molecular medical research on aromatherapy has been steadily increasing for use as an adjuvant therapy in managing psychiatric disorders and to examine its therapeutic mechanisms. Most studies, as well as clinically applied experience, have indicated that various essential oils, such as lavender, lemon and bergamot can help to relieve stress, anxiety, depression and other mood disorders. Most notably, inhalation of essential oils can communicate signals to the olfactory system and stimulate the brain to exert neurotransmitters (e.g. serotonin and dopamine) thereby further regulating mood. However, little research has been done on the molecular mechanisms underlying these effects, thus their mechanism of action remains ambiguous. Several hypotheses have been proposed regarding the therapeutic mechanism of depression. These have mainly centered on possible deficiencies in monoamines, neurotrophins, the neuroendocrine system, c-AMP, cation channels as well as neuroimmune interactions and epigenetics, however the precise mechanism or mechanisms related to depression have yet to be elucidated. In the current study, the effectiveness of aromatherapy for alleviating psychiatric disorders was examined using data collected from previously published studies and our unpublished data. A possible signaling pathway from olfactory system to the central nerve system and the associated key molecular elements of aromatherapy are also proposed. PMID:23531112

  17. CNS Voltage-gated Calcium Channel Gene Variation And Prolonged Recovery Following Sport-related Concussion

    PubMed Central

    McDevitt, Jane

    2016-01-01

    Objectives: To examine the association between concussion duration and two calcium channel, voltage-dependent, R type, alpha 1E subunit (CACNA1E) single nucleotide polymorphisms (i.e., rs35737760 and rs704326). A secondary purpose was to examine the association between CACNA1E single nucleotide polymorphisms (SNPs) and three acute concussion severity scores (i.e., vestibule-ocular reflex test, balance error scoring scale, and Immediate Post-Concussion Assessment and Cognitive Testing). Methods: Forty athletes with a diagnosed concussion from a hospital concussion program completed a standardized initial evaluation. Concussion injury characteristics, acute signs and symptoms followed by an objective screening (i.e., vestibular ocular assessments, balance error scoring system test, and Immediate Post-Concussion Assessment and Cognitive Testing exam) were assessed. Enrolled participants provided salivary samples for isolation of DNA. Two exon SNPs rs35737760 and rs704326 within CACNA1E were genotyped. Results: There was a significant difference found between acute balance deficits and prolonged recovery group (X2 = 5.66, p = 0.017). There was an association found between the dominant model GG genotype (X2 = 5.41, p = 0.027) within the rs704326 SNP and prolonged recovery group. Significant differences were identified for the rs704326 SNP within the dominant model GG genotype (p = 0.030) for VOR scores by recovery. A significant difference was found between the rs704326 SNP codominant model AA (p = 0.042) and visual memory. There was an association between acute balance deficits and prolonged recovery (X2 = 5.66, p = 0.017) for the rs35737760 SNP. No significant associations between concussion severity and genotype for rs35737760 SNP. Conclusion: Athletes carrying the CACNA1E rs704326 homozygous genotype GG are at a greater risk of a prolonged recovery. Athletes that reported balance deficits at the time of injury were more likely to have prolonged recovery. These polymorphisms within CACNA1E could alter the CACNA1E protein and allow for an increase of calcium leading to deficits to the granule cells within the brain.

  18. Potential disadvantages of using socially acquired information.

    PubMed Central

    Giraldeau, Luc-Alain; Valone, Thomas J; Templeton, Jennifer J

    2002-01-01

    The acquisition and use of socially acquired information is commonly assumed to be profitable. We challenge this assumption by exploring hypothetical scenarios where the use of such information either provides no benefit or can actually be costly. First, we show that the level of incompatibility between the acquisition of personal and socially acquired information will directly affect the extent to which the use of socially acquired information can be profitable. When these two sources of information cannot be acquired simultaneously, there may be no benefit to socially acquired information. Second, we assume that a solitary individual's behavioural decisions will be based on cues revealed by its own interactions with the environment. However, in many cases, for social animals the only socially acquired information available to individuals is the behavioural actions of others that expose their decisions, rather than the cues on which these decisions were based. We argue that in such a situation the use of socially acquired information can lead to informational cascades that sometimes result in sub-optimal behaviour. From this theory of informational cascades, we predict that when erroneous cascades are costly, individuals should pay attention only to socially generated cues and not behavioural decisions. We suggest three scenarios that might be examples of informational cascades in nature. PMID:12495513

  19. Lentiviral vectors for treating and modeling human CNS disorders.

    PubMed

    Azzouz, Mimoun; Kingsman, Susan M; Mazarakis, Nicholas D

    2004-09-01

    Vectors based on lentiviruses efficiently deliver genes into many different types of primary neurons from a broad range of species including man and the resulting gene expression is long term. These vectors are opening up new approaches for the treatment of neurological diseases such as Parkinson's disease (PD), Huntington's disease (HD), and motor neuron diseases (MNDs). Numerous animal studies have now been undertaken with these vectors and correction of disease models has been obtained. Lentiviral vectors also provide a new strategy for in vivo modeling of human diseases; for example, the lentiviral-mediated overexpression of mutated human alpha-synuclein or huntingtin genes in basal ganglia induces neuronal pathology in animals resembling PD and HD in man. These vectors have been refined to a very high level and can be produced safely for the clinic. This review will describe the general features of lentiviral vectors with particular emphasis on vectors derived from the non-primate lentivirus, equine infectious anemia virus (EIAV). It will then describe some key examples of genetic correction and generation of genetic animal models of neurological diseases. The prospects for clinical application of lentiviral vectors for the treatment of PD and MNDs will also be outlined. PMID:15352068

  20. GAP-43 promoter elements in transgenic zebrafish reveal a difference in signals for axon growth during CNS development and regeneration.

    PubMed

    Udvadia, A J; Köster, R W; Skene, J H

    2001-04-01

    A pivotal event in neural development is the point at which differentiating neurons become competent to extend long axons. Initiation of axon growth is equally critical for regeneration. Yet we have a limited understanding of the signaling pathways that regulate the capacity for axon growth during either development or regeneration. Expression of a number of genes encoding growth associated proteins (GAPs) accompanies both developmental and regenerative axon growth and has led to the suggestion that the same signaling pathways regulate both modes of axon growth. We have tested this possibility by asking whether a promoter fragment from a well characterized GAP gene, GAP-43, is sufficient to activate expression in both developing and regenerating neurons. We generated stable lines of transgenic zebrafish that express green fluorescent protein (GFP) under regulation of a 1 kb fragment of the rat GAP-43 gene, a fragment that contains a number of evolutionarily conserved elements. Analysis of GFP expression in these lines confirms that the rat 1 kb region can direct growth-associated expression of the transgene in differentiating neurons that extend long axons. Furthermore, this region supports developmental down-regulation of transgene expression which, like the endogenous gene, coincides with neuronal maturation. Strikingly, these same sequences are insufficient for directing expression in regenerating neurons. This finding suggests that signaling pathways regulating axon growth during development and regeneration are not the same. While these results do not exclude the possibility that pathways involved in developmental axon growth are also active in regenerative growth, they do indicate that signaling pathway(s) controlling activation of the GAP-43 gene after CNS injury differ in at least one key component from the signals controlling essential features of developmental axon growth. PMID:11245583

  1. Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation.

    PubMed

    Ou, Sai-Hong Ignatius; Weitz, Michael; Jalas, John R; Kelly, Daniel F; Wong, Vanessa; Azada, Michele C; Quines, Oliver; Klempner, Samuel J

    2016-06-01

    Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment. PMID:27133743

  2. Alzheimer's disease shares gene expression aberrations with purinergic dysregulation of HPRT deficiency (Lesch-Nyhan disease).

    PubMed

    Kang, Tae Hyuk; Friedmann, Theodore

    2015-03-17

    Transcriptomic studies of murine D3 embryonic stem (ES) cells deficient in the purinergic biosynthetic function hypoxanthine guanine phosphoribosyltransferase (HPRT) and undergoing dopaminergic neuronal differentiation has demonstrated a marked shift from neuronal to glial gene expression and aberrant expression of multiple genes also known to be aberrantly expressed in Alzheimer's and other CNS disorders. Such genetic dysregulations may indicate some shared pathogenic metabolic mechanisms in diverse CNS diseases. PMID:25636690

  3. Secretory Leukocyte Protease Inhibitor (SLPI): Emerging Roles in CNS Trauma and Repair.

    PubMed

    Hannila, Sari S

    2015-12-01

    At first glance, secretory leukocyte protease inhibitor (SLPI) would appear to have little relevance to the central nervous system (CNS). This serine protease inhibitor is most commonly found in mucosal fluids such as saliva and is best known for its anti-inflammatory and antimicrobial properties. It has been shown to promote wound healing by reducing expression of pro-inflammatory cytokines, and it can also inhibit bacterial growth and block HIV infection of macrophages. In the past 10 years, however, several studies have reported that SLPI is strongly up-regulated in response to CNS injury and that exogenous administration of SLPI is neuroprotective. It has also been shown that SLPI can overcome inhibition by CNS myelin and promote axonal regeneration. In this review, we will discuss these studies, examine the molecular mechanisms underlying SLPI's effects, and consider SLPI's potential for therapeutic use in cerebral ischemia, spinal cord injury, and multiple sclerosis. PMID:25118190

  4. Preclinical assessment of CNS drug action using eye movements in mice

    PubMed Central

    Cahill, Hugh; Rattner, Amir; Nathans, Jeremy

    2011-01-01

    The drug development process for CNS indications is hampered by a paucity of preclinical tests that accurately predict drug efficacy in humans. Here, we show that a wide variety of CNS-active drugs induce characteristic alterations in visual stimulus–induced and/or spontaneous eye movements in mice. Active compounds included sedatives and antipsychotic, antidepressant, and antiseizure drugs as well as drugs of abuse, such as cocaine, morphine, and phencyclidine. The use of quantitative eye-movement analysis was demonstrated by comparing it with the commonly used rotarod test of motor coordination and by using eye movements to monitor pharmacokinetics, blood-brain barrier penetration, drug-receptor interactions, heavy metal toxicity, pharmacologic treatment in a model of schizophrenia, and degenerative CNS disease. We conclude that eye-movement analysis could complement existing animal tests to improve preclinical drug development. PMID:21821912

  5. Neonatal CNS infection and inflammation caused by Ureaplasma species: rare or relevant?

    PubMed

    Glaser, Kirsten; Speer, Christian P

    2015-02-01

    Colonization with Ureaplasma species has been associated with adverse pregnancy outcome, and perinatal transmission has been implicated in the development of bronchopulmonary dysplasia in preterm neonates. Little is known about Ureaplasma-mediated infection and inflammation of the CNS in neonates. Controversy remains concerning its incidence and implication in the pathogenesis of neonatal brain injury. In vivo and in vitro data are limited. Despite improving care options for extremely immature preterm infants, relevant complications remain. Systematic knowledge of ureaplasmal infection may be of great benefit. This review aims to summarize pathogenic mechanisms, clinical data and diagnostic pitfalls. Studies in preterm and term neonates are critically discussed with regard to their limitations. Clinical questions concerning therapy or prophylaxis are posed. We conclude that ureaplasmas may be true pathogens, especially in preterm neonates, and may cause CNS inflammation in a complex interplay of host susceptibility, serovar pathogenicity and gestational age-dependent CNS vulnerability. PMID:25578885

  6. TDP-43 in CNS development and function: clues to TDP-43-associated neurodegeneration

    PubMed Central

    Sephton, Chantelle F.; Cenik, Basar; Cenik, Bercin Kutluk; Herz, Joachim; Yu, Gang

    2012-01-01

    From the earliest stages of embryogenesis and throughout life, transcriptional regulation is carefully orchestrated in order to generate, shape, and reshape the central nervous system (CNS). TAR DNA-binding protein 43 (TDP-43), is identified as a regulator of essential transcriptional events in the CNS. Evidence for its importance comes from the identification of TDP-43 protein aggregates and genetic mutations in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Efforts are being made to learn more about the biological function of TDP-43 and gain a better understanding of its role in neurodegeneration. TDP-43 RNA targets and protein interactions have now been identified and in vivo evidence shows that TDP-43 is essential in CNS development and function. This review will highlight aspects of these findings. PMID:22944662

  7. Awards, lectures, and fellowships sponsored by the AANS/CNS Section on Tumors.

    PubMed

    Lau, Darryl; Barker, Fred G; Aghi, Manish K

    2014-09-01

    A major goal of the Section on Tumors of the American Association of Neurological Surgery (AANS) and Congress of Neurological Surgeons (CNS) since it was founded in 1984 has been to foster both education and research in the field of brain tumor treatment and development. In support of this goal, the Section sponsors a number of awards, named lectures, and fellowships at the annual meetings of the AANS and CNS. In this article, we describe the awards given by the AANS/CNS Section on Tumors since its foundation, the recipients of the awards, and their philanthropic donors. The subsequent history of awardees and their work is briefly examined. Specifically for the Preuss and Mahaley Awards, this article also examines the rates of publication among the award-winning abstracts and achievement of grant funding by awardees. PMID:24893731

  8. Health-related quality of life of significant others of patients with malignant CNS versus non-CNS tumors: a comparative study.

    PubMed

    Boele, Florien W; Heimans, Jan J; Aaronson, Neil K; Taphoorn, Martin J B; Postma, Tjeerd J; Reijneveld, Jaap C; Klein, Martin

    2013-10-01

    It is often assumed that brain tumor patients' significant others (SOs: partners, other family members or close friends) may face greater stress than those of patients with malignancies not involving the central nervous system (CNS), due to progressive changes in neurological and cognitive functioning. We compared health-related quality of life (HRQOL) of SOs of patients with high-grade glioma (HGG) and low-grade glioma (LGG) with that of SOs of patients with non-CNS tumors with similar prognosis and at a similar phase in the disease trajectory (i.e. non-small cell lung cancer (NSCLC) and low-grade hematological malignancies (NHL/CLL), respectively). HRQOL of SOs and patients was assessed using the Short Form-36 (SF-36) Health Survey. Patients' neurological functioning was indexed and they underwent comprehensive neurocognitive testing. SOs of 213 LGG patients, 99 NHL/CLL patients, 55 HGG patients and 29 NSCLC patients participated. The SOs of LGG and NHL/CLL patients reported similar levels of HRQOL. SOs of HGG patients reported significantly lower mental health scores (MCS; p = 0.041) and social functioning (p = 0.028) than those of NSCLC patients. Mental health scores (MCS) of HGG and NSCLC patients were associated significantly with the mental health of their SOs (p = 0.013 and p < 0.001, respectively). Surprisingly, HGG patients' cognitive and neurological functioning were not predictive of SOs' mental health at the multivariate level. SOs of patients with highly malignant CNS tumors in the acute phase are at increased risk of compromised HRQOL compared to those of patients with systemic tumors without CNS involvement and a comparable life expectancy. PMID:23824535

  9. Can Functional Magnetic Resonance Imaging Improve Success Rates in CNS Drug Discovery?

    PubMed Central

    Borsook, David; Hargreaves, Richard; Becerra, Lino

    2011-01-01

    Introduction The bar for developing new treatments for CNS disease is getting progressively higher and fewer novel mechanisms are being discovered, validated and developed. The high costs of drug discovery necessitate early decisions to ensure the best molecules and hypotheses are tested in expensive late stage clinical trials. The discovery of brain imaging biomarkers that can bridge preclinical to clinical CNS drug discovery and provide a ‘language of translation’ affords the opportunity to improve the objectivity of decision-making. Areas Covered This review discusses the benefits, challenges and potential issues of using a science based biomarker strategy to change the paradigm of CNS drug development and increase success rates in the discovery of new medicines. The authors have summarized PubMed and Google Scholar based publication searches to identify recent advances in functional, structural and chemical brain imaging and have discussed how these techniques may be useful in defining CNS disease state and drug effects during drug development. Expert opinion The use of novel brain imaging biomarkers holds the bold promise of making neuroscience drug discovery smarter by increasing the objectivity of decision making thereby improving the probability of success of identifying useful drugs to treat CNS diseases. Functional imaging holds the promise to: (1) define pharmacodynamic markers as an index of target engagement (2) improve translational medicine paradigms to predict efficacy; (3) evaluate CNS efficacy and safety based on brain activation; (4) determine brain activity drug dose-response relationships and (5) provide an objective evaluation of symptom response and disease modification. PMID:21765857

  10. Drainage of cells and soluble antigen from the CNS to regional lymph nodes.

    PubMed

    Laman, Jon D; Weller, Roy O

    2013-09-01

    Despite the absence of conventional lymphatics, there is efficient drainage of both cerebrospinal fluid (CSF) and interstitial fluid (ISF) from the CNS to regional lymph nodes. CSF drains from the subarachnoid space by channels that pass through the cribriform plate of the ethmoid bone to the nasal mucosa and cervical lymph nodes in animals and in humans; antigen presenting cells (APC) migrate along this pathway to lymph nodes. ISF and solutes drain from the brain parenchyma to cervical lymph nodes by a separate route along 100-150 nm wide basement membranes in the walls of cerebral capillaries and arteries. This pathway is too narrow for the migration of APC so it is unlikely that APC traffic directly from brain parenchyma to lymph nodes by this route. We present a model for the pivotal involvement of regional lymph nodes in immunological reactions of the CNS. The role of regional lymph nodes in immune reactions of the CNS in virus infections, the remote influence of the gut microbiota, multiple sclerosis and stroke are discussed. Evidence is presented for the role of cervical lymph nodes in the induction of tolerance and its influence on neuroimmunological reactions. We look to the future by examining how nanoparticle technology will enhance our understanding of CNS-lymph node connections and by reviewing the implications of lymphatic drainage of the brain for diagnosis and therapy of diseases of the CNS ranging from neuroimmunological disorders to dementias. Finally, we review the challenges and opportunities for progress in CNS-lymph node interactions and their involvement in disease processes. PMID:23695293

  11. Biocompatability of carbon nanotubes with stem cells to treat CNS injuries

    PubMed Central

    Bokara, Kiran Kumar; Kim, Jong Youl; Lee, Young Il; Yun, Kyungeun; Webster, Tom J

    2013-01-01

    Cases reporting traumatic injuries to the brain and spinal cord are extended range of disorders that affect a large percentage of the world's population. But, there are only few effective treatments available for central nervous system (CNS) injuries because the CNS is refractory to axonal regeneration and relatively inaccessible to many pharmacological treatments. The use of stem cell therapy in regenerative medicine has been extensively examined to replace lost cells during CNS injuries. But, given the complexity of CNS injuries oxidative stress, toxic byproducts, which prevails in the microenvironment during the diseased condition, may limit the survival of the transplanted stem cells affecting tissue regeneration and even longevity. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine for the prevention, diagnosis and therapy of certain diseases, including CNS diseases. In particular, the use of CNTs as substrates/scaffolds for supporting the stem cell differentiation has been an area of active research. Single-walled and multi-walled CNT's have been increasingly used as scaffolds for neuronal growth and more recently for neural stem cell growth and differentiation. This review summarizes recent research on the application of CNT-based materials to direct the differentiation of progenitor and stem cells toward specific neurons and to enhance axon regeneration and synaptogenesis for the effective treatment of CNS injuries. Nonetheless, accumulating data support the use of CNTs as a biocompatible and permissive substrate/scaffold for neural cells and such application holds great potential in neurological research. PMID:23869255

  12. Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction

    PubMed Central

    Watterson, D. Martin; Grum-Tokars, Valerie L.; Roy, Saktimayee M.; Schavocky, James P.; Bradaric, Brinda Desai; Bachstetter, Adam D.; Xing, Bin; Dimayuga, Edgardo; Saeed, Faisal; Zhang, Hong; Staniszewski, Agnieszka; Pelletier, Jeffrey C.; Minasov, George; Anderson, Wayne F.; Arancio, Ottavio; Van Eldik, Linda J.

    2013-01-01

    Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for in vivo investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show in vivo efficacy for CNS pathologies, and debates over viable approaches to the development of safe and efficacious kinase inhibitors are unsettled. It is critical, therefore, that these scientific challenges be addressed in order to test hypotheses about protein kinases in neuropathology progression and the potential for in vivo modulation of their catalytic activity. Identification of molecular targets whose in vivo modulation can attenuate synaptic dysfunction would provide a foundation for future disease-modifying therapeutic development as well as insight into cellular mechanisms. Clinical and preclinical studies suggest a critical link between synaptic dysfunction in neurodegenerative disorders and the activation of p38αMAPK mediated signaling cascades. Activation in both neurons and glia also offers the unusual potential to generate enhanced responses through targeting a single kinase in two distinct cell types involved in pathology progression. However, target validation has been limited by lack of highly selective inhibitors amenable to in vivo use in the CNS. Therefore, we employed high-resolution co-crystallography and pharmacoinformatics to design and develop a novel synthetic, active site targeted, CNS-active, p38αMAPK inhibitor (MW108). Selectivity was demonstrated by large-scale kinome screens, functional GPCR agonist and antagonist analyses of off-target potential, and evaluation of cellular target engagement. In vitro and in vivo assays demonstrated that MW108 ameliorates beta-amyloid induced synaptic and cognitive dysfunction. A serendipitous discovery during co-crystallographic analyses revised prevailing models about active site targeting of inhibitors, providing insights that will

  13. Biocompatability of carbon nanotubes with stem cells to treat CNS injuries.

    PubMed

    Bokara, Kiran Kumar; Kim, Jong Youl; Lee, Young Il; Yun, Kyungeun; Webster, Tom J; Lee, Jong Eun

    2013-06-01

    Cases reporting traumatic injuries to the brain and spinal cord are extended range of disorders that affect a large percentage of the world's population. But, there are only few effective treatments available for central nervous system (CNS) injuries because the CNS is refractory to axonal regeneration and relatively inaccessible to many pharmacological treatments. The use of stem cell therapy in regenerative medicine has been extensively examined to replace lost cells during CNS injuries. But, given the complexity of CNS injuries oxidative stress, toxic byproducts, which prevails in the microenvironment during the diseased condition, may limit the survival of the transplanted stem cells affecting tissue regeneration and even longevity. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine for the prevention, diagnosis and therapy of certain diseases, including CNS diseases. In particular, the use of CNTs as substrates/scaffolds for supporting the stem cell differentiation has been an area of active research. Single-walled and multi-walled CNT's have been increasingly used as scaffolds for neuronal growth and more recently for neural stem cell growth and differentiation. This review summarizes recent research on the application of CNT-based materials to direct the differentiation of progenitor and stem cells toward specific neurons and to enhance axon regeneration and synaptogenesis for the effective treatment of CNS injuries. Nonetheless, accumulating data support the use of CNTs as a biocompatible and permissive substrate/scaffold for neural cells and such application holds great potential in neurological research. PMID:23869255

  14. The role of JAK-STAT signaling within the CNS.

    PubMed

    Nicolas, Celine S; Amici, Mascia; Bortolotto, Zuner A; Doherty, Andrew; Csaba, Zsolt; Fafouri, Assia; Dournaud, Pascal; Gressens, Pierre; Collingridge, Graham L; Peineau, Stephane

    2013-01-01

    JAK-STAT is an efficient and highly regulated system mainly dedicated to the regulation of gene expression. Primarily identified as functioning in hematopoietic cells, its role has been found critical in all cell types, including neurons. This review will focus on JAK-STAT functions in the mature central nervous system. Our recent research suggests the intriguing possibility of a non-nuclear role of STAT3 during synaptic plasticity. Dysregulation of the JAK-STAT pathway in inflammation, cancer and neurodegenerative diseases positions it at the heart of most brain disorders, highlighting the importance to understand how it can influence the fate and functions of brain cells. PMID:24058789

  15. Developing highER-throughput zebrafish screens for in-vivo CNS drug discovery.

    PubMed

    Stewart, Adam Michael; Gerlai, Robert; Kalueff, Allan V

    2015-01-01

    The high prevalence of brain disorders and the lack of their efficient treatments necessitate improved in-vivo pre-clinical models and tests. The zebrafish (Danio rerio), a vertebrate species with high genetic and physiological homology to humans, is an excellent organism for innovative central nervous system (CNS) drug discovery and small molecule screening. Here, we outline new strategies for developing higher-throughput zebrafish screens to test neuroactive drugs and predict their pharmacological mechanisms. With the growing application of automated 3D phenotyping, machine learning algorithms, movement pattern- and behavior recognition, and multi-animal video-tracking, zebrafish screens are expected to markedly improve CNS drug discovery. PMID:25729356

  16. Orientia, rickettsia, and leptospira pathogens as causes of CNS infections in Laos: a prospective study

    PubMed Central

    Dittrich, Sabine; Rattanavong, Sayaphet; Lee, Sue J; Panyanivong, Phonepasith; Craig, Scott B; Tulsiani, Suhella M; Blacksell, Stuart D; Dance, David A B; Dubot-Pérès, Audrey; Sengduangphachanh, Amphone; Phoumin, Phonelavanh; Paris, Daniel H; Newton, Paul N

    2015-01-01

    Summary Background Scrub typhus (caused by Orientia tsutsugamushi), murine typhus (caused by Rickettsia typhi), and leptospirosis are common causes of febrile illness in Asia; meningitis and meningoencephalitis are severe complications. However, scarce data exist for the burden of these pathogens in patients with CNS disease in endemic countries. Laos is representative of vast economically poor rural areas in Asia with little medical information to guide public health policy. We assessed whether these pathogens are important causes of CNS infections in Laos. Methods Between Jan 10, 2003, and Nov 25, 2011, we enrolled 1112 consecutive patients of all ages admitted with CNS symptoms or signs requiring a lumbar puncture at Mahosot Hospital, Vientiane, Laos. Microbiological examinations (culture, PCR, and serology) targeted so-called conventional bacterial infections (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, S suis) and O tsutsugamushi, Rickettsia typhi/Rickettsia spp, and Leptospira spp infections in blood or cerebrospinal fluid (CSF). We analysed and compared causes and clinical and CSF characteristics between patient groups. Findings 1051 (95%) of 1112 patients who presented had CSF available for analysis, of whom 254 (24%) had a CNS infection attributable to a bacterial or fungal pathogen. 90 (35%) of these 254 infections were caused by O tsutsugamushi, R typhi/Rickettsia spp, or Leptospira spp. These pathogens were significantly more frequent than conventional bacterial infections (90/1051 [9%] vs 42/1051 [4%]; p<0·0001) by use of conservative diagnostic definitions. CNS infections had a high mortality (236/876 [27%]), with 18% (13/71) for R typhi/Rickettsia spp, O tsutsugamushi, and Leptospira spp combined, and 33% (13/39) for conventional bacterial infections (p=0·076). Interpretation Our data suggest that R typhi/Rickettsia spp, O tsutsugamushi, and Leptospira spp infections are important causes of CNS infections in Laos

  17. Pharmacologic options for CNS infections caused by resistant Gram-positive organisms.

    PubMed

    Peppard, William J; Johnston, Carolyn J; Urmanski, Angela M

    2008-02-01

    Infectious disease continues to evolve, presenting new and challenging clinical situations for practitioners. Specific to device-related and neurosurgical-related CNS infections, Gram-positive organisms are of growing concern. Current Infection Disease Society of America guidelines for the treatment of CNS infections offer little direction after conventional therapy, consisting of vancomycin, has failed or the patient has demonstrated intolerance. A review of literature evaluating alternative therapies, specifically linezolid, quinupristin/dalfopristin, daptomycin and tigecycline, will be presented. Interpretations of these data are offered followed by a brief presentation of future therapies, including ortavancin, telavancin, dalbavancin, ceftobiprole and iclaprim, all of which possess potent Gram-positive activity. PMID:18251666

  18. Verruculogen: a new substance for decreasing of GABA levels in CNS.

    PubMed

    Hotujac, L; Muftić, R H; Filipović, N

    1976-01-01

    In our previous work we examined the mechanism of action of the new tremorogenic substance verruculogen isolated by Cole and coworkers. Examining the effect of various substances with known mechanisms of action on verruculogen-induced tremor, we concluded that this tremor was probably related to decrease of GABA levels in CNS. In order to further define the mechanisms of action of verruculogen, we determined brain GABA levels in animals in which tremor was produced by verruculogen administration. Verruculogen administration produced a decrease in GABA levels in mouse CNS. This finding substantiates our earlier suggestion that verruculogen-induced tremor is mediated by a loss of inhibitory GABA function. PMID:935244

  19. Developing highER-throughput zebrafish screens for in-vivo CNS drug discovery

    PubMed Central

    Stewart, Adam Michael; Gerlai, Robert; Kalueff, Allan V.

    2015-01-01

    The high prevalence of brain disorders and the lack of their efficient treatments necessitate improved in-vivo pre-clinical models and tests. The zebrafish (Danio rerio), a vertebrate species with high genetic and physiological homology to humans, is an excellent organism for innovative central nervous system (CNS) drug discovery and small molecule screening. Here, we outline new strategies for developing higher-throughput zebrafish screens to test neuroactive drugs and predict their pharmacological mechanisms. With the growing application of automated 3D phenotyping, machine learning algorithms, movement pattern- and behavior recognition, and multi-animal video-tracking, zebrafish screens are expected to markedly improve CNS drug discovery. PMID:25729356

  20. Cav1.3 (CACNA1D) L‐type Ca2+ channel dysfunction in CNS disorders

    PubMed Central

    Pinggera, Alexandra

    2016-01-01

    Abstract Cav1.3 belongs to the family of voltage‐gated L‐type Ca2+ channels and is encoded by the CACNA1D gene. Cav1.3 channels are not only essential for cardiac pacemaking, hearing and hormone secretion but are also expressed postsynaptically in neurons, where they shape neuronal firing and plasticity. Recent findings provide evidence that human mutations in the CACNA1D gene can confer risk for the development of neuropsychiatric disease and perhaps also epilepsy. Loss of Cav1.3 function, as shown in knock‐out mouse models and by human mutations, does not result in neuropsychiatric or neurological disease symptoms, whereas their acute selective pharmacological activation results in a depressive‐like behaviour in mice. Therefore it is likely that CACNA1D mutations enhancing activity may be disease relevant also in humans. Indeed, whole exome sequencing studies, originally prompted to identify mutations in primary aldosteronism, revealed de novo CACNA1D missense mutations permitting enhanced Ca2+ signalling through Cav1.3. Remarkably, apart from primary aldosteronism, heterozygous carriers of these mutations also showed seizures and neurological abnormalities. Different missense mutations with very similar gain‐of‐function properties were recently reported in patients with autism spectrum disorders (ASD). These data strongly suggest that CACNA1D mutations enhancing Cav1.3 activity confer a strong risk for – or even cause – CNS disorders, such as ASD. PMID:26842699

  1. Long-term culture and differentiation of CNS precursors derived from anterior human neural rosettes following exposure to ventralizing factors

    SciTech Connect

    Colleoni, Silvia; Giannelli, Serena G.; Armentero, Marie-Therese; Blandini, Fabio; Broccoli, Vania; Lazzari, Giovanna

    2010-04-15

    In this study we demonstrated that neural rosettes derived from human ES cells can give rise either to neural crest precursors, following expansion in presence of bFGF and EGF, or to dopaminergic precursors after exposure to ventralizing factors Shh and FGF8. Both regionalised precursors are capable of extensive proliferation and differentiation towards the corresponding terminally differentiated cell types. In particular, peripheral neurons, cartilage, bone, smooth muscle cells and also pigmented cells were obtained from neural crest precursors while tyrosine hydroxylase and Nurr1 positive dopaminergic neurons were derived from FGF8 and Shh primed rosette cells. Gene expression and immunocytochemistry analyses confirmed the expression of dorsal and neural crest genes such as Sox10, Slug, p75, FoxD3, Pax7 in neural precursors from bFGF-EGF exposed rosettes. By contrast, priming of rosettes with FGF8 and Shh induced the expression of dopaminergic markers Engrailed1, Pax2, Pitx3, floor plate marker FoxA2 and radial glia markers Blbp and Glast, the latter in agreement with the origin of dopaminergic precursors from floor plate radial glia. Moreover, in vivo transplant of proliferating Shh/FGF8 primed precursors in parkinsonian rats demonstrated engraftment and terminal dopaminergic differentiation. In conclusion, we demonstrated the derivation of long-term self-renewing precursors of selected regional identity as potential cell reservoirs for cell therapy applications, such as CNS degenerative diseases, or for the development of toxicological tests.

  2. NF-κB signaling regulates myelination in the CNS

    PubMed Central

    Blank, Thomas; Prinz, Marco

    2014-01-01

    Besides myelination of neuronal axons by oligodendrocytes to facilitate propagation of action potentials, oligodendrocytes also support axon survival and function. A key transcription factor involved in these processes is nuclear factor-κB (NF-κB), a hetero or homodimer of the Rel family of proteins, including p65, c-Rel, RelB, p50, and p52. Under unstimulated, NF-κB remains inactive in the cytoplasm through interaction with NF-κB inhibitors (IκBs). Upon activation of NF-κB the cytoplasmic IκBs gets degradated, allowing the translocation of NF-κB into the nucleus where the dimer binds to the κB consensus DNA sequence and regulates gene transcription. In this review we describe how oligodendrocytes are, directly or indirectly via neighboring cells, regulated by NF-κB signaling with consequences for innate and adaptive immunity and for regulation of cell apoptosis and survival. PMID:24904273

  3. Morphological influence of cellulose nanoparticles (CNs) from cottonseed hulls on rheological properties of polyvinyl alcohol/CN suspensions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This work aims to extract and characterize fibrous, rod-like and spherical cellulose nanoparticles (CNs) from cottonseed hull and to investigate the structure-morphology-rheology relationships. The rheological behavior of poly(vinyl alcohol) (PVA)/CNs suspensions was also examined to guide the solve...

  4. Enhancing Psychosocial Outcomes for Young Adult Childhood CNS Cancer Survivors: Importance of Addressing Vocational Identity and Community Integration

    ERIC Educational Resources Information Center

    Strauser, David R.; Wagner, Stacia; Wong, Alex W. K.

    2012-01-01

    The purpose of this study was to examine the relationship between vocational identity, community integration, positive and negative affect, and satisfaction with life in a group of young adult central nervous system (CNS) cancer survivors. Participants in this study included 45 young adult CNS cancer survivors who ranged in age from 18 to 30 years…

  5. Prospects for Gene Therapy in the Fragile X Syndrome

    ERIC Educational Resources Information Center

    Rattazzi, Mario C.; LaFauci, Giuseppe; Brown, W. Ted

    2004-01-01

    Gene therapy is unarguably the definitive way to treat, and possibly cure, genetic diseases. A straightforward concept in theory, in practice it has proven difficult to realize, even when directed to easily accessed somatic cell systems. Gene therapy for diseases in which the central nervous system (CNS) is the target organ presents even greater…

  6. The choroid plexus—a multi-role player during infectious diseases of the CNS

    PubMed Central

    Schwerk, Christian; Tenenbaum, Tobias; Kim, Kwang Sik; Schroten, Horst

    2015-01-01

    The choroid plexus (CP) is the source of cerebrospinal fluid (CSF) production and location of the blood-CSF barrier (BCSFB), which is constituted by the epithelial cells of the CP. Several infectious pathogens including viruses, bacteria, fungi and parasites cross the BCSFB to enter the central nervous system (CNS), ultimately leading to inflammatory infectious diseases like meningitis and meningoencephalitis. The CP responds to this challenge by the production of chemokines and cytokines as well as alterations of the barrier function of the BCSFB. During the course of CNS infectious disease host immune cells enter the CNS, eventually contributing to the cellular damage caused by the disease. Additional complications, which are in certain cases caused by choroid plexitis, can arise due to the response of the CP to the pathogens. In this review we will give an overview on the multiple functions of the CP during brain infections highlighting the CP as a multi-role player during infectious diseases of the CNS. In this context the importance of tools for investigation of these CP functions and a possible suitability of the CP as therapeutic target will be discussed. PMID:25814932

  7. Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

    PubMed Central

    Sanchez-Covarrubias, Lucy; Slosky, Lauren M.; Thompson, Brandon J.; Davis, Thomas P.; Ronaldson, Patrick T.

    2014-01-01

    The blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from “brute force” approaches to delivering drugs by physically circumventing brain barriers towards chemical approaches that can target specific compounds of the BBB and/or BCSF barrier. However, our understanding of transporters at the BBB and BCSF barriers has primarily focused on understanding efflux transporters that efficiently prevent drugs from attaining therapeutic concentrations in the CNS. Recently, through the characterization of multiple endogenously expressed uptake transporters, this paradigm has shifted to the study of brain transporter targets that can facilitate drug delivery (i.e., influx transporters). Additionally, signaling pathways and trafficking mechanisms have been identified for several endogenous BBB/BCSF transporters, thereby offering even more opportunities to understand how transporters can be exploited for optimization of CNS drug delivery. This review presents an overview of the BBB and BCSF barrier as well as the many families of transporters functionally expressed at these barrier sites. Furthermore, we present an overview of various strategies that have been designed and utilized to deliver therapeutic agents to the brain with a particular emphasis on those approaches that directly target endogenous BBB/BCSF barrier transporters. PMID:23789948

  8. Solitary Fibrous Tumor/Hemangiopericytoma Dichotomy Revisited: A Restless Family of Neoplasms in the CNS.

    PubMed

    Yalcin, Can Ege; Tihan, Tarik

    2016-03-01

    Solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) both entered the literature as separate entities in the early to mid 1900s. In contrast to their central nervous system (CNS) counterparts, there has been a tendency to consider these 2 entities as 1 since the early 1990s, as soft tissue SFT gradually included the tumors previously diagnosed as HPC. The most recent World Health Organization (WHO) classification of the tumors of soft tissue considered the term HPC obsolete, and places all such tumors within the extrapleural SFT category. In contrast, CNS SFT and HPC continue to be regarded as different entities in the latest version of the WHO CNS tumor classification. A change in this approach is currently being considered for the upcoming revision of the WHO scheme, but it is not quite clear whether such a change will be as drastic as the one adopted by the soft tissue and bone tumor working group. This article focuses on the historical evolution of these 2 labels as primary CNS neoplasms, and reviews their differences and similarities in terms of clinical, pathologic, and molecular features. PMID:26849816

  9. CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases.

    PubMed

    Kerrn-Jespersen, B M; Lindelof, M; Illes, Zsolt; Blaabjerg, Morten; Lund, E L; Klausen, C; Christiansen, I; Sellebjerg, F; Kondziella, D

    2014-08-15

    Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt-and-pepper" appearance on MRI, and 3) angiocentric, predominantly T-lymphocytic infiltration as revealed by brain biopsy. Inflammatory diseases including neuroinfections, CNS lymphoma and neurosarcoidosis must be excluded. Since CLIPPERS was described in 2010, many patients might have been misdiagnosed in the past. We therefore searched medical records from a large tertiary neurological center, the Department of Neurology at Rigshospitalet, Copenhagen University Hospital, for patients discharged between 1999 and 2013 with a diagnosis of "sarcoidosis with other localization", "other acute disseminating demyelination", "other demyelinating disease in the CNS" or "encephalitis, myelitis or encephalomyelitis". Of 206 identified patients, 24 had been examined by brain biopsy and were included for further evaluation. Following clinical, neuroradiological and neuropathological review, 3 patients (12.5%) were reclassified as having CLIPPERS. Median long-term follow-up was 75 months. The present results suggest that clinical re-evaluation of patients previously diagnosed with unspecified inflammatory demyelinating CNS disease or atypical neurosarcoidosis may increase the detection rate of CLIPPERS. Further, potentially severe neurological deficits and progressive parenchymal atrophy on MRI may suggest neurodegenerative features, which emphasizes the need for early immunomodulatory treatment. PMID:24954086

  10. BBB-targeting, protein-based nanomedicines for drug and nucleic acid delivery to the CNS.

    PubMed

    Peluffo, Hugo; Unzueta, Ugutz; Negro-Demontel, María Luciana; Xu, Zhikun; Váquez, Esther; Ferrer-Miralles, Neus; Villaverde, Antonio

    2015-01-01

    The increasing incidence of diseases affecting the central nervous system (CNS) demands the urgent development of efficient drugs. While many of these medicines are already available, the Blood Brain Barrier and to a lesser extent, the Blood Spinal Cord Barrier pose physical and biological limitations to their diffusion to reach target tissues. Therefore, efforts are needed not only to address drug development but specially to design suitable vehicles for delivery into the CNS through systemic administration. In the context of the functional and structural versatility of proteins, recent advances in their biological fabrication and a better comprehension of the physiology of the CNS offer a plethora of opportunities for the construction and tailoring of plain nanoconjugates and of more complex nanosized vehicles able to cross these barriers. We revise here how the engineering of functional proteins offers drug delivery tools for specific CNS diseases and more transversally, how proteins can be engineered into smart nanoparticles or 'artificial viruses' to afford therapeutic requirements through alternative administration routes. PMID:25698504

  11. Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency

    ERIC Educational Resources Information Center

    Moretti, Paolo; Peters, Sarika U.; del Gaudio, Daniela; Sahoo, Trilochan; Hyland, Keith; Bottiglieri, Teodoro; Hopkin, Robert J.; Peach, Elizabeth; Min, Sang Hee; Goldman, David; Roa, Benjamin; Bacino, Carlos A.; Scaglia, Fernando

    2008-01-01

    We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects…

  12. Pharmacological Evaluation of Naproxen Metal Complexes on Antinociceptive, Anxiolytic, CNS Depressant, and Hypoglycemic Properties

    PubMed Central

    Das, Narhari; Abdur Rahman, S. M.

    2016-01-01

    Purpose. The present study was designed to investigate the antinociceptive, anxiolytic, CNS depressant, and hypoglycemic effects of the naproxen metal complexes. Methods. The antinociceptive activity was evaluated by acetic acid-induced writhing method and radiant heat tail-flick method while anxiolytic activity was evaluated by elevated plus maze model. The CNS depressant activity of naproxen metal complexes was assessed using phenobarbitone-induced sleeping time test and the hypoglycemic test was performed using oral glucose tolerance test. Results. Metal complexes significantly (P < 0.001) reduced the number of abdominal muscle contractions induced by 0.7% acetic acid solution in a dose dependent manner. At the dose of 25 mg/kg body weight p.o. copper, cobalt, and zinc complexes exhibited higher antinociceptive activity having 59.15%, 60.56%, and 57.75% of writhing inhibition, respectively, than the parent ligand naproxen (54.93%). In tail-flick test, at both doses of 25 and 50 mg/kg, the copper, cobalt, silver, and zinc complexes showed higher antinociceptive activity after 90 minutes than the parent drug naproxen. In elevated plus maze (EPM) model the cobalt and zinc complexes of naproxen showed significant anxiolytic effects in dose dependent manner, while the copper, cobalt, and zinc complexes showed significant CNS depressant and hypoglycemic activity. Conclusion. The present study demonstrated that copper, cobalt, and zinc complexes possess higher antinociceptive, anxiolytic, CNS depressant, and hypoglycemic properties than the parent ligand. PMID:27478435

  13. Immunohistological localization of 5-HT in the CNS and feeding system of the Stable Fly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    5-HT immunoreactive neurons were detected in the CNS of the stable fly. The finding of strong innervations of the cibarial pump muscles and the foregut by 5-HT IR neurons in the feeding-related systems suggests that 5-HT may play a crucial role in the control of the feeding behavior in both the larv...

  14. Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS.

    PubMed

    Omura, Takao; Omura, Kumiko; Tedeschi, Andrea; Riva, Priscilla; Painter, Michio W; Rojas, Leticia; Martin, Joshua; Lisi, Véronique; Huebner, Eric A; Latremoliere, Alban; Yin, Yuqin; Barrett, Lee B; Singh, Bhagat; Lee, Stella; Crisman, Tom; Gao, Fuying; Li, Songlin; Kapur, Kush; Geschwind, Daniel H; Kosik, Kenneth S; Coppola, Giovanni; He, Zhigang; Carmichael, S Thomas; Benowitz, Larry I; Costigan, Michael; Woolf, Clifford J

    2015-06-01

    Axon regeneration in the CNS requires reactivating injured neurons' intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater sprouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. Inhibition of Activin signaling in CAST/Ei mice diminishes their CNS regenerative capacity, whereas its activation in C57BL/6 animals boosts regeneration. This screen demonstrates that mammalian CNS regeneration can occur and reveals a molecular pathway that contributes to this ability. PMID:26004914

  15. The allometry of CNS size and consequences of miniaturization in orb-weaving and cleptoparasitic spiders.

    PubMed

    Quesada, Rosannette; Triana, Emilia; Vargas, Gloria; Douglass, John K; Seid, Marc A; Niven, Jeremy E; Eberhard, William G; Wcislo, William T

    2011-11-01

    Allometric studies of the gross neuroanatomy of adults from nine species of spiders from six web-weaving families (Orbicularia), and nymphs from six of these species, show that very small spiders resemble other small animals in having disproportionately larger central nervous systems (CNSs) relative to body mass when compared with large-bodied forms. Small spiderlings and minute adult spiders have similar relative CNS volumes. The relatively large CNS of a very small spider occupies up to 78% of the cephalothorax volume. The CNSs of very small spiders extend into their coxae, occupying as much as 26% of the profile area of the coxae of an Anapisona simoni spiderling (body mass < 0.005 mg). Such modifications occur both in species with minute adults, and in tiny spiderlings of species with large-bodied adults. In at least one such species, Leucauge mariana, the CNS of the spiderling extends into a prominent ventral bulge of the sternum. Tiny spiders also have reduced neuronal cell body diameters. The adults of nearly all orbicularian spiders weave prey capture webs, as do the spiderlings, beginning with second instar nymphs. Comparable allometric relations occur in adults of both orb-weaving and cleptoparasitic species, indicating that this behavioral difference is not reflected in differences in gross CNS allometry. PMID:22036838

  16. Pharmacological Evaluation of Naproxen Metal Complexes on Antinociceptive, Anxiolytic, CNS Depressant, and Hypoglycemic Properties.

    PubMed

    Hasan, Md Sharif; Das, Narhari; Al Mahmud, Zobaer; Abdur Rahman, S M

    2016-01-01

    Purpose. The present study was designed to investigate the antinociceptive, anxiolytic, CNS depressant, and hypoglycemic effects of the naproxen metal complexes. Methods. The antinociceptive activity was evaluated by acetic acid-induced writhing method and radiant heat tail-flick method while anxiolytic activity was evaluated by elevated plus maze model. The CNS depressant activity of naproxen metal complexes was assessed using phenobarbitone-induced sleeping time test and the hypoglycemic test was performed using oral glucose tolerance test. Results. Metal complexes significantly (P < 0.001) reduced the number of abdominal muscle contractions induced by 0.7% acetic acid solution in a dose dependent manner. At the dose of 25 mg/kg body weight p.o. copper, cobalt, and zinc complexes exhibited higher antinociceptive activity having 59.15%, 60.56%, and 57.75% of writhing inhibition, respectively, than the parent ligand naproxen (54.93%). In tail-flick test, at both doses of 25 and 50 mg/kg, the copper, cobalt, silver, and zinc complexes showed higher antinociceptive activity after 90 minutes than the parent drug naproxen. In elevated plus maze (EPM) model the cobalt and zinc complexes of naproxen showed significant anxiolytic effects in dose dependent manner, while the copper, cobalt, and zinc complexes showed significant CNS depressant and hypoglycemic activity. Conclusion. The present study demonstrated that copper, cobalt, and zinc complexes possess higher antinociceptive, anxiolytic, CNS depressant, and hypoglycemic properties than the parent ligand. PMID:27478435

  17. The choroid plexus-a multi-role player during infectious diseases of the CNS.

    PubMed

    Schwerk, Christian; Tenenbaum, Tobias; Kim, Kwang Sik; Schroten, Horst

    2015-01-01

    The choroid plexus (CP) is the source of cerebrospinal fluid (CSF) production and location of the blood-CSF barrier (BCSFB), which is constituted by the epithelial cells of the CP. Several infectious pathogens including viruses, bacteria, fungi and parasites cross the BCSFB to enter the central nervous system (CNS), ultimately leading to inflammatory infectious diseases like meningitis and meningoencephalitis. The CP responds to this challenge by the production of chemokines and cytokines as well as alterations of the barrier function of the BCSFB. During the course of CNS infectious disease host immune cells enter the CNS, eventually contributing to the cellular damage caused by the disease. Additional complications, which are in certain cases caused by choroid plexitis, can arise due to the response of the CP to the pathogens. In this review we will give an overview on the multiple functions of the CP during brain infections highlighting the CP as a multi-role player during infectious diseases of the CNS. In this context the importance of tools for investigation of these CP functions and a possible suitability of the CP as therapeutic target will be discussed. PMID:25814932

  18. Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

    PubMed Central

    Williams, Jessica L.; Holman, David W.; Klein, Robyn S.

    2014-01-01

    In the adult central nervous system (CNS), chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier (BBB) including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX3CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease. PMID:24920943

  19. Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells

    PubMed Central

    Dileepan, Thamotharampillai; Smith, Erica D.; Knowland, Daniel; Hsu, Martin; Platt, Maryann; Bittner-Eddy, Peter; Cohen, Brenda; Southern, Peter; Latimer, Elizabeth; Harley, Earl; Agalliu, Dritan; Cleary, P. Patrick

    2015-01-01

    Group A streptococcal (GAS) infection induces the production of Abs that cross-react with host neuronal proteins, and these anti-GAS mimetic Abs are associated with autoimmune diseases of the CNS. However, the mechanisms that allow these Abs to cross the blood-brain barrier (BBB) and induce neuropathology remain unresolved. We have previously shown that GAS infection in mouse models induces a robust Th17 response in nasal-associated lymphoid tissue (NALT). Here, we identified GAS-specific Th17 cells in tonsils of humans naturally exposed to GAS, prompting us to explore whether GAS-specific CD4+ T cells home to mouse brains following i.n. infection. Intranasal challenge of repeatedly GAS-inoculated mice promoted migration of GAS-specific Th17 cells from NALT into the brain, BBB breakdown, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins under conditions in which no viable bacteria were detected in CNS tissue. CD4+ T cells were predominantly located in the olfactory bulb (OB) and in other brain regions that receive direct input from the OB. Together, these findings provide insight into the immunopathology of neuropsychiatric complications that are associated with GAS infections and suggest that crosstalk between the CNS and cellular immunity may be a general mechanism by which infectious agents exacerbate symptoms associated with other CNS autoimmune disorders. PMID:26657857

  20. Genome Sequence Analysis of Staphylococcus equorum Bovine Mastitis Isolate UMC-CNS-924

    PubMed Central

    Calcutt, Michael J.; Foecking, Mark F.; Hsieh, Hsin-Yeh; Perry, Jeanette; Stewart, George C.

    2013-01-01

    Intramammary infections in dairy cattle are frequently caused by staphylococci, resulting in mastitis and associated economic losses. A draft genome sequence was determined for Staphylococcus equorum UMC-CNS-924, isolated from the milk of a Holstein cow, to better understand the genetic basis of its pathogenesis and adaptation to the bovine mammary gland. PMID:24136848

  1. Obesity and Risk for Brain/CNS Tumors, Gliomas and Meningiomas: A Meta-Analysis

    PubMed Central

    Sergentanis, Theodoros N.; Tsivgoulis, Georgios; Perlepe, Christina; Ntanasis-Stathopoulos, Ioannis; Tzanninis, Ioannis-Georgios; Sergentanis, Ioannis N.; Psaltopoulou, Theodora

    2015-01-01

    Objective This meta-analysis aims to examine the association between being overweight/obese and risk of meningiomas and gliomas as well as overall brain/central nervous system (CNS) tumors. Study Design Potentially eligible publications were sought in PubMed up to June 30, 2014. Random-effects meta-analysis and dose-response meta-regression analysis was conducted. Cochran Q statistic, I-squared and tau-squared were used for the assessment of between-study heterogeneity. The analysis was performed using Stata/SE version 13 statistical software. Results A total of 22 studies were eligible, namely 14 cohort studies (10,219 incident brain/CNS tumor cases, 1,319 meningioma and 2,418 glioma cases in a total cohort size of 10,143,803 subjects) and eight case-control studies (1,009 brain/CNS cases, 1,977 meningioma cases, 1,265 glioma cases and 8,316 controls). In females, overweight status/obesity was associated with increased risk for overall brain/CNS tumors (pooled RR = 1.12, 95%CI: 1.03–1.21, 10 study arms), meningiomas (pooled RR = 1.27, 95%CI: 1.13–1.43, 16 study arms) and gliomas (pooled RR = 1.17, 95%CI: 1.03–1.32, six arms). Obese (BMI>30 kg/m2) females seemed particularly aggravated in terms of brain/CNS tumor (pooled RR = 1.19, 95%CI: 1.05–1.36, six study arms) and meningioma risk (pooled RR = 1.48, 95%CI: 1.28–1.71, seven arms). In males, overweight/obesity status correlated with increased meningioma risk (pooled RR = 1.58, 95%CI: 1.22–2.04, nine study arms), whereas the respective association with overall brain/CNS tumor or glioma risk was not statistically significant. Dose-response meta-regression analysis further validated the findings. Conclusion Our findings highlight obesity as a risk factor for overall brain/CNS tumors, meningiomas and gliomas among females, as well as for meningiomas among males. PMID:26332834

  2. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

    SciTech Connect

    Vuillemenot, Brian R.; Kennedy, Derek; Reed, Randall P.; Boyd, Robert B.; Butt, Mark T.; Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O'Neill, Charles A.

    2014-05-15

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

  3. Identical rearranged forms of JC polyomavirus transcriptional control region in plasma and cerebrospinal fluid of acquired immunodeficiency syndrome patients with progressive multifocal leukoencephalopathy.

    PubMed

    Fedele, Cesare Giovanni; Ciardi, Maria Rosa; Delia, Salvatore; Contreras, Gerardo; Perez, José Luis; De Oña, Maria; Vidal, Elisa; Tenorio, Antonio

    2003-10-01

    Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by the human polyomavirus JC (JCV). JCV has a hypervariable noncoding transcriptional control region (TCR) that spans the origin of replication of the JCV genome through to the first ATG start codon for late gene transcription. The archetype form of TCR is frequently found in the urine and kidneys of healthy and immunocompromised subjects. However the rearranged forms, whose prototype is Mad-1, possibly generated by deletion and duplication of segments of the archetype sequence, are found in the brain and cerebrospinal fluid (CSF) of PML patients. In this study the authors compared JCV TCR detected in paired CSF, plasma, and urine samples of 11 acquired immunodeficiency syndrome (AIDS) patients affected by PML to try to determine where the rearranged JCV TCRs are selected. In one patient, it was also possible to amplify and sequence the TCR in the brain and lymphocytes. Moreover, in 5/11 patients, the CSF, plasma, and urine samples corresponding to 2 months after PML development were available; and in another patient, it was possible to sequence the TCR in plasma and lymphocytes sampled 8 months before the onset of PML. The presence of the same TCR sequences in all the CSF and plasma samples taken from individual patients could strengthen the hypothesis that the blood is a compartment where JCV may replicate and undergo rearrangement of the TCR. This further supports the hypothesis that JCV reaches the brain by a hematogenous route and indicates that the JCV TCR sequences detected in plasma could be used as an early marker of JCV pathogenicity before the clinical appearance of PML in immunocompromised patients. PMID:13129769

  4. ED-12WIDESPREAD SYSTEMIC METASTASES FROM MEDULLOBLASTOMA WITHOUT EVIDENCE OF ACTIVE CNS INVOLVEMENT: A CASE SERIES

    PubMed Central

    Kumthekar, Priya; Singh, Simran; Smiley, Natasha Pillay; Lulla, Rishi

    2014-01-01

    This case series describes two patients with previously treated medulloblastoma who present with systemic metastases without evidence of central nervous system (CNS) disease. Patient #1 is male who presented at age 29 with pathology confirmed medulloblastoma treated with complete surgical resection followed by radiation (36 Gy craniospinal plus posterior fossa boost). Subsequently, he received cisplatin, cytoxan, and vincristine. One year later, he developed back pain and urinary retention. Imaging of his spine showed widespread bony metastases without parenchymal CNS disease. Biopsy of the left acetabulum confirmed metastatic medulloblastoma. He is currently enrolled on study with LDE225 versus temozolomide. Surveillance imaging to date is negative for intracranial metastasis, but does show extensive bony metastases involving the total spine, pelvis, ribs, sternum, clavicles, humeri, and femurs. Patient #2 is a female who presented at 32 years with severe headaches, nausea and vomiting found to have pathology confirmed medulloblastoma. She was lost to follow up temporarily, but presented again months later with headaches. She had a recurrent mass and underwent repeat resection. MRI of the spine showed nodular enhancement of the sacral nerve roots compatible with leptomeningeal spread. She underwent craniospinal radiation 36 Gy with a boost to the lumbar region and posterior fossa. One year after initial diagnosis, she presented with hypotension, tachycardia, and fatigue. Neuroimaging showed improved enhancement of the sacral nerve roots and brain imaging showed stable postsurgical changes. Systemic imaging, however, revealed widespread metastatic disease in the lymphatic system, liver, lung, and bones. The patient passed away a few months later. Medulloblastoma can metastasize outside the central nervous system (CNS), however typically does so concurrently with CNS progression. Here we present two adult patients with widely metastatic medulloblastoma systemically

  5. Alcohol intake alters immune responses and promotes CNS viral persistence in mice.

    PubMed

    Loftis, Jennifer M; Taylor, Jonathan; Raué, Hans-Peter; Slifka, Mark K; Huang, Elaine

    2016-10-01

    Chronic hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic effects, including central nervous system (CNS) damage and neuropsychiatric impairments. Alcohol abuse can exacerbate these adverse effects on brain and behavior, but the molecular mechanisms are not well understood. This study investigated the role of alcohol in regulating viral persistence and CNS immunopathology in mice infected with lymphocytic choriomeningitis virus (LCMV), a model for HCV infections in humans. Female and male BALB/c mice (n=94) were exposed to alcohol (ethanol; EtOH) and water (or water only) using a two-bottle choice paradigm, followed one week later by infection with either LCMV clone 13 (causes chronic infection similar to chronic HCV), LCMV Armstrong (causes acute infection), or vehicle. Mice were monitored for 60days post-infection and continued to receive 24-h access to EtOH and water. Animals infected with LCMV clone 13 drank more EtOH, as compared to those with an acute or no viral infection. Six weeks after infection with LCMV clone 13, mice with EtOH exposure evidenced higher serum viral titers, as compared to mice without EtOH exposure. EtOH intake was also associated with reductions in virus-specific CD8(+) T cell frequencies (particularly CD11a(hi) subsets) and evidence of persistent CNS viremia in chronically infected mice. These findings support the hypothesis that EtOH use and chronic viral infection can result in combined toxic effects accelerating CNS damage and neuropsychiatric dysfunction and suggest that examining the role of EtOH in regulating viral persistence and CNS immunopathology in mice infected with LCMV can lead to a more comprehensive understanding of comorbid alcohol use disorder and chronic viral infection. PMID:27269869

  6. Differentiation between meningiomas and other CNS tumors by simultaneous somatostatin receptor and brain scintigraphy

    SciTech Connect

    Haldemann, A.R.; Luescher, D.; Sulzer, M.

    1994-05-01

    Since the differentiation between meningiomas and some other CNS tumors may be difficult in certain localizations, biopsy is mandatory, even in patients with meningiomas who are to be treated with percutaneous radiotherapy alone. The high density of somatostatin receptors (SSR) in meningiomas has led us to compare patients with meningiomas and other CNS tumors by simultaneous SSR and brain scintigraphy (BS) using 74 MBq 111In octreotide and 740 MBq 99mTc DTPA injected two hours later. SPECT was performed on a 3-head gamma camera 4 hours after 111In octreotide injection in multiple peak acquisition mode in 35 patients with radiologically documented CNS tumors. In positive scans, a tumor ROI was defined manually in the transverse 111In slice with highest tumor contrast and the identical tumor ROI was transferred to the corresponding 99mTc slice. A SSR to BS index was then calculated from the ratio of 111In to 99mTc counts after normalizing for identical total counts in the slices. in negative scans, the SSR to BS index was set to be 1.0. In 7 meningiomas, the SSR to BS index was 2.64{plus_minus}0.76. In 28 other CNS tumors (7 gliomas I-111, 4 neurinomas, 3 glial reactions, 3 metastases, 3 gliomas IV, 2 ependymomas, 1 chordoma, 1 NHL; plus 4 inoperable, radiologically diagnosed glioblastomas) 1.06{plus_minus}0.13. Thus, a highly significant difference was found between these two groups (p<0.0001). It is concluded that combined SSR and BS allows excellent discrimination between meningiomas and other CNS tumors and may become a non-invasive alternative to biopsy in selected clinical situations.

  7. Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology.

    PubMed

    Marques, Andrea Horvath; Bjørke-Monsen, Anne-Lise; Teixeira, Antônio L; Silverman, Marni N

    2015-08-18

    Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying

  8. Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS

    PubMed Central

    Franssen, Elske H. P.; Zhao, Rong-Rong; Koseki, Hiroaki; Kanamarlapudi, Venkateswarlu; Hoogenraad, Casper C.

    2015-01-01

    Integrins are adhesion and survival molecules involved in axon growth during CNS development, as well as axon regeneration after injury in the peripheral nervous system (P